Human serum albumin based nanocarriers for immunotherapy

Abstract

The present invention relates to a mannose-HSA based nanocarrier system, and a pharmaceutical composition containing the same for delivery of immunomodulatory drugs. The present invention further relates to a method of manufacturing said mannose-HSA nanocarrier system.

Description

[0001] Human Serum Albumin based nanocarriers for immunotherapy

[0002] Specification

[0003] The present invention relates to a mannose-HSA based nanocarrier system for drug delivery, and a pharmaceutical composition containing the same for delivery of immunomodulatory drugs into target cells expressing surface mannose receptors, e.g. into the liver. Therefore, said mannose-HSA based nanocarrier system and the pharmaceutical composition thereof are particularly useful in the treatment and / or prevention of diseases affecting liver function and liver structure. The present invention further relates to a method of manufacturing said mannose- HSA nanocarrier system.

[0004] Background of the invention

[0005] The present disclosure is broadly concerned with drug delivery systems. More particularly, it is concerned with mannose-HSA based protein carrier that carries multiple copies of drugs for immunotherapy.

[0006] Immunotherapy has emerged as a new treatment regime for a wide variety of diseases ranging from autoimmune disorders and cancer to fibrosis. In cancer immunotherapies, the major objective is to train the immune system to eliminate cancer cells and to combat metastases. Chronic inflammatory diseases such as liver inflammation can result in fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Vaccination and immune therapy using checkpoint inhibitors or immune system modulators, have been proposed as treatment options. Yet, major drawbacks of small molecule drugs for immunotherapy and chronic inflammatory diseases include low response rate and uncontrolled, systemic immune responses (Rana, I., et al., 2023. Nanocarriers for cancer nano-immunotherapy. Drug Deliv. and Transl. Res. 13, 1936-1954). Consequently, the effects can extend to healthy cells and this leads to adverse side effects throughout a patient's body.

[0007] Nano-sized drug delivery systems improve the solubility of drugs, bioavailability and their systemic circulation time. These drug-loaded nanoparticles can reach and accumulate into tumors because of the so-called enhanced permeability and retention (EPR) effect of many solid tumors. Besides tumors, drug-loaded nanoparticles could also accumulate in other types of body tissues that possess an open vasculature, for example in the liver and the spleen, which is a particularly promising target for nanoparticles loaded with immunomodulatory drugs, as they comprise of many antigen presenting cells.

[0008] Liposome nanoparticles are the standards in drug delivery, with various systems already approved for use by FDA / EMA, e.g. Doxil,® Comirnaty®. Nevertheless, systemic immune responses and systemic toxicity are still observed in liposome systems. Furthermore, despite preclinical models showing promising results, the clinical efficacy of nano-sized drug delivery is limited due to heterogeneity of the EPR effects, interstitial fluid pressure. Systems to boost uptake of their therapeutic agents into the affected tissues, where it can be most effective, is required. In addition, the controlled release delivery of pharmaceutical agents to targeted sites such as tumors and areas of inflammation is important to prevent unwanted toxicity to healthy cells and tissues.

[0009] In immunotherapy, nanoparticle carrier systems are loaded with active ingredients such as mRNA, DNA or an antigen or / and an immunomodulatory drug that can stimulate antigen presentation by target antigen presenting cells to induce a strong and specific activation of anti-tumor T cells. Biopolymers such as proteins and carbohydrates offer biocompatibility and biodegradability and could be good candidates as nanocamers. Human serum albumin, a major protein in human blood, has been used as a nanocamer in FDA-approved nanoformulation, Abraxane®. There are various studies which show that albumin is accumulated in tumor-bearing mice. On the other hand, certain immune cells are known to present high density of C-type lectin receptors and this interaction can be exploited to boost the uptake for the active drug ingredient.

[0010] Therefore, given the limitations of existing nanocamers, a targeted drug delivery system and / or composition for immune diseases, that can preferentially deliver high loading of active pharmaceutical ingredients to the diseased sites and release them in a controlled fashion to achieve high efficacy and minimize systemic toxicity, is required. Such a nano-size pharmaceutical composite should direct the accumulation of a drug directly into the affected tissue in a highly concentrated manner for immunotherapy.

[0011] Prakash et al. (Int. J. Cancer: 126, 1966-1981 (2010)) report on a mannose-6- phosphate-HSA-doxorubicin conjugate targeting the mannose-6- phosphate / insulin-like growth factor receptor (M6P / IGF-IIR). The authors could show that the conjugate releases doxorubicin at lysosomal pH and specifically binds and internalizes into M6P / IGF-IIR-expressing B16 melanoma cells. In vivo, the conjugate distributes to tumors and some other organs, in contrast to free doxorubicin which distribute to all organs but slightly to tumors. The mannose-6- phosphate-HSA-doxorubicin conjugate does not show any side-effects on liver and kidney function tests, body weight and blood cell counts and inhibits tumor growth in B16 tumor-bearing mice.

[0012] Smith et al. (Biomacromolecules 2020, 21 , 3704-3712) investigated the use of PEG-PLA nanoparticles (NPs) presenting potent Toll-like receptor 7 / 8 agonists (TLR7 / 8a) to enhance anti-PD-L1 immunotherapy in cancer treatment. TLR7 / 8a- PEG-PLA and mannose-PEG-PLA block co-polymers were physically mixed at different ratios with unmodified PEG-PLA and the nanoparticles were precipitated. In in vitro studies, the authors could demonstrate that tethering TLR7 / 8a to the surface of the PEG-PLA NPs slightly decreases the potency of the molecule in vitro and co-presentation of mannose on the NP surface does not significantly alter the potency of the construct. In fact, the free TLR7 / 8a agonist (a Resiquimod derivative) showed lower ECso value and a similar maximum activation in comparison with TLR7 / 8a-PEG-PLA nanoparticles of medium or high TLR7 / 8a agonist valency. In a murine colon adenocarcinoma model, peritumoral injection of TLR7 / 8a PEG-PLA NPs (without mannose) resulted in slowed down tumor growth, extended survival, and decreased systemic toxicity in comparison to the free TLR7 / 8a.

[0013] Fei-Fei et al. (Theranostics 2017; 7(15):3667-3689) review preparation methods for albumin-based nanoparticles for multifunctional bioimaging and drug delivery. The authors note that a single albumin possesses long blood circulation and high biocompatibility, which facilitate the maintenance of high blood drug concentration for long periods, and conclude that a single albumin could be used as a scaffold to be functionalized for effective drug delivery and bioimaging.

[0014] Wagener et al. (Adv. Therap. 2020, 3, 1900185) studied liposomes bearing the oligosaccharide trimannose on their surface, for their ability to address DCs in vitro and in vivo. It was found that the trimannosylated polyether lipids increasingly accumulated in spleen, liver, and BM, compared to the nonmannosylated polyether lipids. For the liposomal formulations, this effect was even more pronounced. The present invention solves the above problem by providing a fully biopolymerbased nanocarrier with excellent performance that addresses previous limitations and enables targeted modulation of a set of immune cells, which play a key role in many immune-related conditions.

[0015] The objective of the present invention is solved by the teaching of the independent claims. Further advantageous features, aspects and details of the invention are evident from the dependent claims, the description, the figures, and the examples of the present application.

[0016] Brief description of the invention

[0017] The present invention is directed to an HSA-nanocarrier system for drug delivery, wherein said nanocamer system comprises:

[0018] A) a human serum albumin (HSA);

[0019] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0020] C) at least one immunomodulatory drug covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the at least one immunomodulatory drug is not doxorubicin.

[0021] The inventive HSA nanocamer system is particularly effective in delivering the immunomodulatory drug to a specific cell or tissue by active targeting.

[0022] In other words, the present invention is directed to an HSA-nanocarrier system for active-targeting drug delivery, wherein said nanocarrier system comprises:

[0023] A) a human serum albumin (HSA);

[0024] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0025] C) at least one immunomodulatory drug covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the at least one immunomodulatory drug is not doxorubicin. Reworded, the present invention is directed to an HSA-nanocarrier system for organ targeting drug delivery, particularly liver, wherein said nanocamer system comprises:

[0026] A) a human serum albumin (HSA);

[0027] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0028] C) at least one immunomodulatory drug covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the at least one immunomodulatory drug is not doxorubicin.

[0029] Reworded, the present invention is directed to an HSA-nanocarrier system for liver targeting drug delivery, wherein said nanocarrier system comprises:

[0030] A) a human serum albumin (HSA);

[0031] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0032] C) at least one immunomodulatory drug covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the at least one immunomodulatory drug is not doxorubicin.

[0033] All HSA-nanocarrier systems for drug delivery as disclosed herein are most preferably for liver targeting drug delivery.

[0034] In preferred embodiments, the HSA-nanocarrier system for drug delivery, comprises:

[0035] A) a human serum albumin (HSA);

[0036] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0037] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering.

[0038] In preferred embodiments, the HSA-nanocarrier system for liver-targeted drug delivery, comprises:

[0039] A) a human serum albumin (HSA); B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0040] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering.

[0041] In preferred embodiments, the HSA-nanocamer system for drug delivery, comprises

[0042] A) a human serum albumin (HSA);

[0043] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0044] C) at least one immunomodulatory drug covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose or dimannose or trimannose moieties is covalently bound to said HSA via an interconnecting molecule comprising polyethylene glycol with a number of ethylene glycol repeating units between 2 and 10, and wherein the at least one immunomodulatory drug is not doxorubicin.

[0045] In preferred embodiments, the HSA-nanocamer system for drug delivery, comprises

[0046] A) a human serum albumin (HSA);

[0047] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0048] C) at least one immunomodulatory drug covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose or dimannose or trimannose moieties is covalently bound to said HSA via an interconnecting molecule selected from NHS-DBCO, NHS-PEGn-DBCO, BCN-Endo-NHS, BCN-Endo-PEGn-NHS, NHS-DIBO, NHS- PEGn-DIBO, NHS-DIFO, NHS-PEGn-DIFO, NHS-BCN, NHS-PEGn-BCN, NHS- TCO, NHS-PEGn-TCO, NHS-alkyne, NHS-PEGn-alkyne, NHS-azide, NHS-PEGn- Azide, STP-DBCO, STP-PEGn-DBCO, BCN-Endo-STP, BCN-Endo-PEGn-STP, STP-DIBO, STP-PEGn-DIBO, STP-DIFO, STP-PEGn-DIFO, STP-BCN, STP- PEGn-BCN, STP-TCO, STP-PEGn-TCO, STP-alkyne, STP-PEGn-alkyne, STP- azide, STP-PEGn-Azide, TFP-DBCO, TFP-PEGn-DBCO, BCN-Endo-TFP, BCN- Endo-PEGn-TFP, TFP-DIBO, TFP-PEGn-DIBO, TFP-DIFO, TFP-PEGn-DIFO, TFP-BCN, TFP-PEGn-BCN, TFP-TCO, TFP-PEGn-TCO, TFP-alkyne, TFP-PEGn- alkyne, TFP-azide, TFP-PEGn-Azide, PTP-DBCO, PTP-PEGn-DBCO, BCN-Endo- PTP, BCN-Endo-PEGn-PTP, PTP-DIBO, PTP-PEGn-DIBO, PTP-DIFO, PTP- PEGn-DIFO, PTP-BCN, PTP-PEGn-BCN, PTP-TCO, PTP-PEGn-TCO, PTP- alkyne, PTP-PEGn-alkyne, PTP-azide, PTP-PEGn-Azide, NPC-DBCO, NPC- PEGn-DBCO, BCN-Endo-NPC, BCN-Endo-PEGn-NPC, NPC-DIBO, NPC-PEGn- DIBO, NPC-DIFO, NPC-PEGn-DIFO, NPC-BCN, NPC-PEGn-BCN, NPC-TCO, NPC-PEGn-TCO, NPC-alkyne, NPC-PEGn-alkyne, NPC-azide, NPC-PEGn-Azide, NCS-azide, NCS-PEGn-azide, NCS-alkyne, NCS-PEGn-alkyne, NCS-DBCO, NCS-PEGn-DBCO, BCN-Endo-NCS, BCN-Endo-PEGn-NCS, NCS-DIBO, NCS- PEGn-DIBO, NCS-DIFO, NCS-PEGn-DIFO, NCS-BCN, NCS-PEGn-BCN, DBCO- COOH, DBCO-PEGn-COOH, BCN-Endo-COOH, BCN-Endo-PEGn-COOH, BCN- COOH, BCN-PEGn-COOH, DIBO-COOH, DIBO-PEGn-COOH, DIFO-COOH, DIFO-PEGn-COOH, Alkyne-COOH, an Alkyne-PEGn-COOH, wherein n represents the number of ethylene glycol repeating units between 2 and 10, and wherein the at least one immunomodulatory drug is not doxorubicin.

[0049] In preferred embodiments, the HSA-nanocamer system for drug delivery, comprises

[0050] A) a human serum albumin (HSA);

[0051] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0052] C) at least one immunomodulatory drug covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties are selected from the group consisting of ManpNs, ManpsNs, (Manp)3N3, and (Manp3)3N3, preferably ManpsNs, and wherein the at least one immunomodulatory drug is not doxorubicin.

[0053] In preferred embodiments, the HSA-nanocamer system for drug delivery, comprises

[0054] A) a human serum albumin (HSA);

[0055] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0056] C) at least one immunomodulatory drug covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the at least one immunomodulatory drug is covalently bound to said HSA via a drug linker selected from pyridinyldithio ethyl carbonate, pyridinyldithio-propionyl- hydrazide, pyridyldithio-ethylamine, SPDP, SPP, SPDB, pyridyldithio-PEGn-NHS, DMAC-SPDP, DMAC-SPP, pyridinyldithio-PEGn-carboxylic acid, PDB-PFP, PDEC-NB, PPC-NB, maleim ide-carboxylic acid, maleimide-amide-PEGn-va- PABC-PNP, maleimide-PEGn-vc-PABC-PNP, mc-vc-PABC-PNP, mc-Val-Cit-PAB- Cl, mcc-vc-PAPC-PNP, mcc-PEGn-PABC, mc-va linker, mcc-va linker, mc-va-nhs linker, mcc-va-nhs linker, mc-Gly-Gly-Phe-Gly-PABC, maleimide-hydrazide, vinylsulfone-carbonate, thiosulfonate linker, hydrazide-maleimide linker, iodoacetamide linker, and methanethiosulfonate linker, and wherein the at least one immunomodulatory drug is not doxorubicin.

[0057] In preferred embodiments, the HSA-nanocamer system for drug delivery, comprises

[0058] A) a human serum albumin (HSA);

[0059] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0060] C) at least one immunomodulatory drug covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the molar ratio of the plurality of monomannose or dimannose or trimannose moieties to HSA is comprised between 1 and 59, and wherein the at least one immunomodulatory drug is not doxorubicin.

[0061] In preferred embodiments, the HSA-nanocamer system for drug delivery, comprises

[0062] A) a human serum albumin (HSA);

[0063] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0064] C) at least one immunomodulatory drug covalently bound to said HSA;

[0065] D) a fluorescent dye covalently bound to said HSA, wherein the fluorescent dye comprises a maleimide as thiol-reactive functional group or an NHS- ester as amine-reactive functional group, and wherein the fluorescent dye emits light in a range of 400 nm to 850 nm; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the fluorescent dye is a fluorescent dye maleimide selected from the group consisting of sulfo-cyanin-maleimide, Alexa Fluor-maleimide, and cyanin-maleimide., and wherein the at least one immunomodulatory drug is not doxorubicin.

[0066] In preferred embodiments, the HSA-nanocarrier system for drug delivery, comprises

[0067] A) a human serum albumin (HSA);

[0068] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0069] C) at least one immunomodulatory drug covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the HSA is denatured, and wherein the at least one immunomodulatory drug is not doxorubicin.

[0070] Thus, the present invention is also directed to an HSA-nanocarrier system for drug delivery, comprising:

[0071] A) a human serum albumin (HSA);

[0072] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0073] C) at least one immunomodulatory drug covalently bound to said HSA, wherein the at least one immunomodulatory drug is not doxorubicin; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering.

[0074] Preferably, the HSA-nanocarrier system for drug delivery, comprises:

[0075] A) a human serum albumin (HSA);

[0076] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0077] C) at least one immunomodulatory drug covalently bound to said HSA, wherein the at least one immunomodulatory drug is not doxorubicin; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an interconnecting molecule comprising polyethylene glycol with a number of ethylene glycol repeating units between 2 and 10.

[0078] Preferably, the HSA-nanocarrier system for drug delivery, comprises: A) a human serum albumin (HSA);

[0079] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0080] C) at least one immunomodulatory drug covalently bound to said HSA, wherein the at least one immunomodulatory drug is not doxorubicin; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an NHS-PEGn-DBCO interconnecting molecule.

[0081] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0082] A) a human serum albumin (HSA);

[0083] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0084] C) at least one immunomodulatory drug covalently bound to said HSA, wherein the at least one immunomodulatory drug is not doxorubicin; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an interconnecting molecule selected from NHS- DBCO, NHS-PEGn-DBCO, BCN-Endo-NHS, BCN-Endo-PEGn-NHS, NHS-DIBO, NHS-PEGn-DIBO, NHS-DIFO, NHS-PEGn-DIFO, NHS-BCN, NHS-PEGn-BCN, NHS-TCO, NHS-PEGn-TCO, NHS-alkyne, NHS-PEGn-alkyne, NHS-azide, NHS- PEGn-Azide, STP-DBCO, STP-PEGn-DBCO, BCN-Endo-STP, BCN-Endo-PEGn- STP, STP-DIBO, STP-PEGn-DIBO, STP-DIFO, STP-PEGn-DIFO, STP-BCN, STP-PEGn-BCN, STP-TCO, STP-PEGn-TCO, STP-alkyne, STP-PEGn-alkyne, STP-azide, STP-PEGn-Azide, TFP-DBCO, TFP-PEGn-DBCO, BCN-Endo-TFP, BCN-Endo-PEGn-TFP, TFP-DIBO, TFP-PEGn-DIBO, TFP-DIFO, TFP-PEGn- DIFO, TFP-BCN, TFP-PEGn-BCN, TFP-TCO, TFP-PEGn-TCO, TFP-alkyne, TFP- PEGn-alkyne, TFP-azide, TFP-PEGn-Azide, PTP-DBCO, PTP-PEGn-DBCO, BCN-Endo-PTP, BCN-Endo-PEGn-PTP, PTP-DIBO, PTP-PEGn-DIBO, PTP- DIFO, PTP-PEGn-DIFO, PTP-BCN, PTP-PEGn-BCN, PTP-TCO, PTP-PEGn- TCO, PTP-alkyne, PTP-PEGn-alkyne, PTP-azide, PTP-PEGn-Azide, NPC-DBCO, NPC-PEGn-DBCO, BCN-Endo-NPC, BCN-Endo-PEGn-NPC, NPC-DIBO, NPC- PEGn-DIBO, NPC-DIFO, NPC-PEGn-DIFO, NPC-BCN, NPC-PEGn-BCN, NPC- TCO, NPC-PEGn-TCO, NPC-alkyne, NPC-PEGn-alkyne, NPC-azide, NPC-PEGn- Azide, NCS-azide, NCS-PEGn-azide, NCS-alkyne, NCS-PEGn-alkyne, NCS- DBCO, NCS-PEGn-DBCO, BCN-Endo-NCS, BCN-Endo-PEGn-NCS, NCS-DIBO, NCS-PEGn-DIBO, NCS-DIFO, NCS-PEGn-DIFO, NCS-BCN, NCS-PEGn-BCN, DBCO-COOH, DBCO-PEGn-COOH, BCN-Endo-COOH, BCN-Endo-PEGn- COOH, BCN-COOH, BCN-PEGn-COOH, DIBO-COOH, DIBO-PEGn-COOH, DIFO-COOH, DIFO-PEGn-COOH, Alkyne-COOH, and Alkyne-PEGn-COOH, wherein n represents the number of ethylene glycol repeating units between 2 and 10.

[0085] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0086] A) a human serum albumin (HSA);

[0087] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0088] C) at least one immunomodulatory drug covalently bound to said HSA, wherein the at least one immunomodulatory drug is not doxorubicin; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, and wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an NHS-PEGn-DBCO interconnecting molecule, and the molar ratio of the interconnecting molecule to HSA is comprised between 3 and 59, and / or wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59.

[0089] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0090] A) a human serum albumin (HSA);

[0091] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0092] C) at least one immunomodulatory drug covalently bound to said HSA, wherein the at least one immunomodulatory drug is not doxorubicin; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an NHS-PEGn-DBCO interconnecting molecule, and the molar ratio of the interconnecting molecule to HSA is comprised between 3 and 59, wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59, wherein the molar ratio of the immunomodulatory drug to HSA is comprised between 1 and 30, and wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties are selected from the group consisting of ManpNs, ManpsNs, (Manp)3N3, and (Manp3)3N3, preferably ManpsNs. Preferably, the HSA-nanocarrier system for drug delivery, comprises:

[0093] A) a human serum albumin (HSA);

[0094] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0095] C) at least one immunomodulatory drug covalently bound to said HSA, wherein the at least one immunomodulatory drug is not doxorubicin; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an interconnecting molecule comprising polyethylene glycol with a number of ethylene glycol repeating units between 2 and 10, and the molar ratio of the interconnecting molecule to HSA is comprised between 3 and 59, wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59, wherein the molar ratio of the immunomodulatory drug to HSA is comprised between 1 and 30, and wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties are selected from the group consisting of ManpNs, ManpsNs, (Manp)3N3, and (Manp3)3N3, preferably ManpsNs, and wherein the HSA bound to the plurality of mannose moieties and to the at least one immunomodulatory drug is backfolded by a rapid dilution step.

[0096] Preferably, the HSA-nanocarrier system for drug delivery, comprises:

[0097] A) a human serum albumin (HSA);

[0098] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0099] C) at least one immunomodulatory drug covalently bound to said HSA, wherein the at least one immunomodulatory drug is not doxorubicin; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an NHS-PEGn-DBCO interconnecting molecule, and the molar ratio of the interconnecting molecule to HSA is comprised between 3 and 59, wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59, wherein the molar ratio of the immunomodulatory drug to HSA is comprised between 1 and 30, and wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties are selected from the group consisting of ManpNs, ManpsNs, (Manp)3N3, and (Manp3)3N3, preferably ManpsNs, and wherein the HSA bound to the plurality of mannose moieties and to the at least one immunomodulatory drug is backfolded by a rapid dilution step.

[0100] Another embodiment is directed to a pharmaceutical composition comprising the HSA nanocarrier system for drug delivery, comprising

[0101] A) a human serum albumin (HSA);

[0102] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0103] C) at least one immunomodulatory drug covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the at least one immunomodulatory drug is not doxorubicin, and a pharmaceutical acceptable excipient.

[0104] Another aspect of the present invention is directed to a method to manufacture a HSA nanocarrier system for drug delivery, comprising

[0105] A) a human serum albumin (HSA);

[0106] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0107] C) at least one immunomodulatory drug covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the method comprises the following steps: i.) providing monomolecular native HSA, wherein the monomolecular native

[0108] HSA is optionally labeled with a fluorescent dye; ii.) attaching an interconnecting molecule to the HSA; iii.) covalently binding of a plurality of monomannose or dimannose or trimannose moieties to the interconnecting molecule to obtain mannosylated HSA; iv.) denaturing of the mannosylated HSA obtained at step iii.; v.-a) covalently binding of at least one immunomodulatory drug to said denatured mannosylated HSA, wherein the one or more immunomodulatory drugs are attached to a drug linker comprising a thiol-reactive functional group; v.-b) capping of unreacted thiols, preferably with N-ethylmaleimide; v.-c) washing the denatured nanocarrier system obtained in step v.-b; vi.) backfolding of the denatured nanocarrier system via rapid dilution procedure; vii.) obtaining a monomolecular HSA nanocarrier system, wherein the at least one immunomodulatory drug is not doxorubicin.

[0109] In preferred embodiments, the method to manufacture a HSA nanocamer system for drug delivery, comprising

[0110] A) a human serum albumin (HSA);

[0111] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0112] C) at least one immunomodulatory drug covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the method comprises the following steps: i.) providing monomolecular native HSA, wherein the monomolecular native

[0113] HSA is optionally labeled with a fluorescent dye; ii.) attaching an interconnecting molecule to the HSA; iii.) covalently binding of a plurality of monomannose or dimannose or trimannose moieties to the interconnecting molecule to obtain mannosylated HSA; iv.) denaturing of the mannosylated HSA obtained at step iii.; v.-a) covalently binding of at least one immunomodulatory drug selected from a

[0114] TLR agonist or a STAT3 inhibitor to said denatured mannosylated HSA, wherein the one or more immunomodulatory drugs are attached to a drug linker comprising a thiol-reactive functional group; v.-b) capping of unreacted thiols, preferably with N-ethylmaleimide; v.-c) washing the denatured nanocarrier system obtained in step v.-b; vi.) backfolding of the denatured nanocarrier system via rapid dilution procedure; vii.) obtaining a monomolecular HSA nanocamer system.

[0115] In preferred embodiments of the method to manufacture a HSA nanocamer system for drug delivery as described herein, the plurality of monomannose or dimannose or trimannose moieties is covalently bound to said HSA via an interconnecting molecule comprising polyethylene glycol with a number of ethylene glycol repeating units between 2 and 10.

[0116] In preferred embodiments the method to manufacture a HSA nanocamer system for drug delivery, comprising

[0117] A) a human serum albumin (HSA); B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0118] C) at least one immunomodulatory drug covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the method comprises the following steps: i.) providing monomolecular native HSA, wherein the monomolecular native

[0119] HSA is optionally labeled with a fluorescent dye; ii.) attaching an interconnecting molecule to the HSA; iii.) covalently binding of a plurality of monomannose or dimannose or trimannose moieties to the interconnecting molecule to obtain mannosylated HSA; iv.) denaturing of the mannosylated HSA obtained at step iii.; v.-a) covalently binding of at least one immunomodulatory drug to said denatured mannosylated HSA, wherein the one or more immunomodulatory drugs are attached to a drug linker comprising a thiol-reactive functional group; v.-b) capping of unreacted thiols, preferably with N-ethylmaleimide; v.-c) washing the denatured nanocarrier system obtained in step v.-b; vi.) backfolding of the denatured nanocarrier system via rapid dilution procedure; vii.) obtaining a monomolecular HSA nanocamer system, wherein the at least one immunomodulatory drug is not doxorubicin, and wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties are selected from the group consisting of ManpNs, ManpsNs, (Manp)3N3, and (Manp3)3N3, preferably ManpsNs.

[0120] In preferred embodiments of the method to manufacture a HSA nanocamer system for drug delivery as described herein, the at least one immunomodulatory drug is covalently bound to said HSA by a drug linker selected from pyridinyldithio ethyl carbonate, pyridinyldithio-propionyl-hydrazide, pyridyldithio-ethylamine, SPDP, SPP, SPDB, pyridyldithio-PEGn-NHS, DMAC-SPDP, DMAC-SPP, pyridinyldithio-PEGn-carboxylic acid, PDB-PFP, PDEC-NB, PPC-NB, maleimide- carboxylic acid, maleimide-amide-PEGn-va-PABC-PNP, maleimide-PEGn-vc- PABC-PNP, mc-vc-PABC-PNP, mc-Val-Cit-PAB-CI, mcc-vc-PAPC-PNP, mcc- PEGn-PABC, mc-va linker, mcc-va linker, mc-va-nhs linker, mcc-va-nhs linker, mc-Gly-Gly-Phe-Gly-PABC, maleimide-hydrazide, vinylsulfone-carbonate, thiosulfonate linker, hydrazide-maleimide linker, iodoacetamide linker, and methanethiosulfonate linker. In preferred embodiments the method to manufacture a HSA nanocamer system for drug delivery, comprising

[0121] A) a human serum albumin (HSA);

[0122] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0123] C) at least one immunomodulatory drug covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the method comprises the following steps: i.) providing monomolecular native HSA, wherein the monomolecular native HSA is optionally labeled with a fluorescent dye; i.1 ) subjecting the HSA labeled with a fluorescent dye maleimide to a ringopening hydrolysis by adding a buffer at a pH above 9; ii.) attaching an interconnecting molecule to the HSA; iii.) covalently binding of a plurality of monomannose or dimannose or trimannose moieties to the interconnecting molecule to obtain mannosylated HSA; iv.) denaturing of the mannosylated HSA obtained at step iii.; v.-a) covalently binding of at least one immunomodulatory drug to said denatured mannosylated HSA, wherein the one or more immunomodulatory drugs are attached to a drug linker comprising a thiol-reactive functional group; v.-b) capping of unreacted thiols, preferably with N-ethylmaleimide; v.-c) washing the denatured nanocarrier system obtained in step v.-b; vi.) backfolding of the denatured nanocarrier system via rapid dilution procedure; vii.) obtaining a monomolecular HSA nanocamer system, wherein the at least one immunomodulatory drug is not doxorubicin.

[0124] In preferred embodiments, the at least one immunomodulatory drug is covalently bound the HSA, when the HSA is in a denatured state and afterwards backfolded by rapid dilution. Thus, the present invention is also directed to an HSA-nanocarrier system for drug delivery, wherein said nanocarrier system comprises:

[0125] A) a human serum albumin (HSA);

[0126] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA; C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, and wherein the HSA bound to the plurality of mannose-based targeting structures and to the at least one immunomodulatory drug is backfolded by a rapid dilution step.

[0127] In regard to all HSA-nanocarrier systems disclosed herein the mannose moiety is preferably a trimannose moiety so that B) reads for all HSA-nanocarrier systems disclosed herein preferably as follows:

[0128] B) a plurality of monomannose moieties or trimannose moieties covalently bound to said HSA; or

[0129] B) a plurality of dimannose moieties or trimannose moieties covalently bound to said HSA; or most preferably

[0130] B) a plurality of trimannose moieties covalently bound to said HSA.

[0131] In another embodiment, the HSA nanocarrier system comprises a plurality of monomannose moieties, dimannose moieties, or trimannose moieties selected from the group consisting of ManpNs, ManpsNs, (Manp)3N3, and (Manp3)3N3. Thus, the present invention is also directed to an

[0132] HSA-nanocarrier system for drug delivery, wherein said nanocarrier system comprises:

[0133] A) a human serum albumin (HSA);

[0134] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0135] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, and wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties are selected from the group consisting of ManpNs, ManpsNs, (Manp)3N3, and (Manp3)3N3.

[0136] Most preferably, the plurality of mannose moieties is ManpsNs (trimannose).

[0137] Preferably, the HSA-nanocarrier system for drug delivery comprises: A) a human serum albumin (HSA);

[0138] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0139] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is selected from the group consisting of ManpNs, ManpsNs, (Manp)3N3, and (Manp3)3N3 and wherein the HSA bound to the plurality of mannose moieties and to the at least one immunomodulatory drug is backfolded by a rapid dilution step.

[0140] In another embodiment, the HSA nanocamer system comprises a molar immunomodulatory drug:HSA ratio between 1 and 30. Thus, the present invention is also directed to an HSA-nanocamer system for drug delivery, comprising:

[0141] A) a human serum albumin (HSA);

[0142] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0143] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, and wherein the molar ratio of the immunomodulatory drug to HSA is comprised between 1 and 30.

[0144] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0145] A) a human serum albumin (HSA);

[0146] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0147] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the molar ratio of the immunomodulatory drug to HSA is comprised between 1 and 30, and the plurality of monomannose moieties, dimannose moieties, or trimannose moieties are selected from the group consisting of ManpNs, ManpsNs, (Manp)3N3, and (Manp3)3N3, preferably ManpsNs.

[0148] Preferably, the HSA-nanocamer system for drug delivery, comprises: A) a human serum albumin (HSA); B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0149] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the molar ratio of the immunomodulatory drug to HSA is comprised between 1 and 30, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties are selected from the group consisting of ManpNs, ManpsNs, (Manp)3N3, and (Manp3)3N3, preferably ManpsNs, and wherein the HSA bound to the monomannose moieties, dimannose moieties, or trimannose moieties and to the at least one immunomodulatory drug is backfolded by a rapid dilution step.

[0150] In another embodiment, the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59. Thus, the present invention is also directed to an HSA-nanocamer system for drug delivery, comprising:

[0151] A) a human serum albumin (HSA);

[0152] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0153] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, and wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59.

[0154] In another embodiment, the HSA nanocarrier system comprises a plurality of monomannose or dimannose or trimannose moieties covalently bound to the HSA via an interconnecting molecule, wherein the molar ratio of interconnecting molecule to HSA is comprised between 3 and 59, and / or wherein the molar ratio of the plurality of monomannose or dimannose or trimannose moieties to HSA is comprised between 1 and 59. Thus, the present invention is also directed to an HSA-nanocamer system for drug delivery, comprising:

[0155] A) a human serum albumin (HSA);

[0156] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0157] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, and wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an interconnecting molecule and the molar ratio of the interconnecting molecule to HSA is comprised between 3 and 59, and / or wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59.

[0158] In a preferred embodiment, the HSA-nanocamer system for drug delivery, comprises:

[0159] A) a human serum albumin (HSA);

[0160] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0161] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, and wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an interconnecting molecule and the molar ratio of the interconnecting molecule to HSA is comprised between 3 and 59, and wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59.

[0162] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0163] A) a human serum albumin (HSA);

[0164] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0165] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an interconnecting molecule and the molar ratio of the interconnecting molecule to HSA is comprised between 3 and 59, wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59, wherein the molar ratio of the immunomodulatory drug to HSA is comprised between 1 and 30, and wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties are selected from the group consisting of ManpNs, ManpsNs, (Manp)3N3, and (Manps^Ns, preferably ManpsNs.

[0166] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0167] A) a human serum albumin (HSA);

[0168] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0169] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an interconnecting molecule and the molar ratio of the interconnecting molecule to HSA is comprised between 3 and 59, wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59, wherein the molar ratio of the immunomodulatory drug to HSA is comprised between 1 and 30, and wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties are selected from the group consisting of ManpNs, ManpsNs, (Manp)3N3, and (Manps^Ns, preferably ManpsNs, and wherein the HSA bound to the plurality of mannose moieties and to the at least one immunomodulatory drug is backfolded by a rapid dilution step.

[0170] In another embodiment, the HSA nanocarrier system comprises a plurality of monomannose or dimannose or trimannose moieties covalently bound to the HSA via an interconnecting molecule comprising polyethylene glycol with a number of ethylene glycol repeating units between 2 and 10. Thus, the present invention is also directed to an HSA-nanocamer system for drug delivery, comprising:

[0171] A) a human serum albumin (HSA);

[0172] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0173] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an interconnecting molecule comprising polyethylene glycol with a number of ethylene glycol repeating units between 2 and 10. Preferably, the HSA-nanocarrier system for drug delivery, comprises:

[0174] A) a human serum albumin (HSA);

[0175] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0176] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, and wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an interconnecting molecule comprising polyethylene glycol with a number of ethylene glycol repeating units between 2 and 10, and the molar ratio of the interconnecting molecule to HSA is comprised between 3 and 59, and / or wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59.

[0177] In a preferred embodiment, the HSA-nanocarrier system for drug delivery, comprises:

[0178] A) a human serum albumin (HSA);

[0179] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0180] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, and wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an interconnecting molecule comprising polyethylene glycol with a number of ethylene glycol repeating units between 2 and 10, and the molar ratio of the interconnecting molecule to HSA is comprised between 3 and 59, and wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59

[0181] Preferably, the HSA-nanocarrier system for drug delivery, comprises:

[0182] A) a human serum albumin (HSA);

[0183] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0184] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an interconnecting molecule comprising polyethylene glycol with a number of ethylene glycol repeating units between 2 and 10, and the molar ratio of the interconnecting molecule to HSA is comprised between 3 and 59, wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59, wherein the molar ratio of the immunomodulatory drug to HSA is comprised between 1 and 30, and wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties are selected from the group consisting of ManpNs, ManpsNs, (Manp)3N3, and (Manp3)3N3, preferably ManpsNs.

[0185] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0186] A) a human serum albumin (HSA);

[0187] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0188] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an interconnecting molecule comprising polyethylene glycol with a number of ethylene glycol repeating units between 2 and 10, and the molar ratio of the interconnecting molecule to HSA is comprised between 3 and 59, wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59, wherein the molar ratio of the immunomodulatory drug to HSA is comprised between 1 and 30, and wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties are selected from the group consisting of ManpNs, ManpsNs, (Manp)3N3, and (Manp3)3N3, preferably ManpsNs, and wherein the HSA bound to the plurality of mannose moieties and to the at least one immunomodulatory drug is backfolded by a rapid dilution step.

[0189] In another embodiment, the HSA nanocarrier system comprises a plurality of monomannose or dimannose or trimannose moieties covalently bound to the HSA via an interconnecting molecule selected from NHS-DBCO, NHS-PEGn-DBCO, BCN-Endo-NHS, BCN-Endo-PEGn-NHS, NHS-DIBO, NHS-PEGn-DIBO, NHS- DIFO, NHS-PEGn-DIFO, NHS-BCN, NHS-PEGn-BCN, NHS-TCO, NHS-PEGn- TCO, NHS-alkyne, NHS-PEGn-alkyne, NHS-azide, NHS-PEGn-Azide, STP- DBCO, STP-PEGn-DBCO, BCN-Endo-STP, BCN-Endo-PEGn-STP, STP-DIBO, STP-PEGn-DIBO, STP-DIFO, STP-PEGn-DIFO, STP-BCN, STP-PEGn-BCN, STP-TCO, STP-PEGn-TCO, STP-alkyne, STP-PEGn-alkyne, STP-azide, STP- PEGn-Azide, TFP-DBCO, TFP-PEGn-DBCO, BCN-Endo-TFP, BCN-Endo-PEGn- TFP, TFP-DIBO, TFP-PEGn-DIBO, TFP-DIFO, TFP-PEGn-DIFO, TFP-BCN, TFP- PEGn-BCN, TFP-TCO, TFP-PEGn-TCO, TFP-alkyne, TFP-PEGn-alkyne, TFP- azide, TFP-PEGn-Azide, PTP-DBCO, PTP-PEGn-DBCO, BCN-Endo-PTP, BCN- Endo-PEGn-PTP, PTP-DIBO, PTP-PEGn-DIBO, PTP-DIFO, PTP-PEGn-DIFO, PTP-BCN, PTP-PEGn-BCN, PTP-TCO, PTP-PEGn-TCO, PTP-alkyne, PTP- PEGn-alkyne, PTP-azide, PTP-PEGn-Azide, NPC-DBCO, NPC-PEGn-DBCO, BCN-Endo-NPC, BCN-Endo-PEGn-NPC, NPC-DIBO, NPC-PEGn-DIBO, NPC- DIFO, NPC-PEGn-DIFO, NPC-BCN, NPC-PEGn-BCN, NPC-TCO, NPC-PEGn- TCO, NPC-alkyne, NPC-PEGn-alkyne, NPC-azide, NPC-PEGn-Azide, NCS-azide, NCS-PEGn-azide, NCS-alkyne, NCS-PEGn-alkyne, NCS-DBCO, NCS-PEGn- DBCO, BCN-Endo-NCS, BCN-Endo-PEGn-NCS, NCS-DIBO, NCS-PEGn-DIBO, NCS-DIFO, NCS-PEGn-DIFO, NCS-BCN, NCS-PEGn-BCN, DBCO-COOH, DBCO-PEGn-COOH, BCN-Endo-COOH, BCN-Endo-PEGn-COOH, BCN-COOH, BCN-PEGn-COOH, DIBO-COOH, DIBO-PEGn-COOH, DIFO-COOH, DIFO- PEGn-COOH, Alkyne-COOH, and Alkyne-PEGn-COOH, wherein n represents the number of ethylene glycol repeating units between 2 and 10. Thus, the present invention is also directed to an HSA-nanocamer system for drug delivery, comprising:

[0190] A) a human serum albumin (HSA);

[0191] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0192] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an interconnecting molecule selected from NHS- DBCO, NHS-PEGn-DBCO, BCN-Endo-NHS, BCN-Endo-PEGn-NHS, NHS-DIBO, NHS-PEGn-DIBO, NHS-DIFO, NHS-PEGn-DIFO, NHS-BCN, NHS-PEGn-BCN, NHS-TCO, NHS-PEGn-TCO, NHS-alkyne, NHS-PEGn-alkyne, NHS-azide, NHS- PEGn-Azide, STP-DBCO, STP-PEGn-DBCO, BCN-Endo-STP, BCN-Endo-PEGn- STP, STP-DIBO, STP-PEGn-DIBO, STP-DIFO, STP-PEGn-DIFO, STP-BCN, STP-PEGn-BCN, STP-TCO, STP-PEGn-TCO, STP-alkyne, STP-PEGn-alkyne, STP-azide, STP-PEGn-Azide, TFP-DBCO, TFP-PEGn-DBCO, BCN-Endo-TFP, BCN-Endo-PEGn-TFP, TFP-DIBO, TFP-PEGn-DIBO, TFP-DIFO, TFP-PEGn- DIFO, TFP-BCN, TFP-PEGn-BCN, TFP-TCO, TFP-PEGn-TCO, TFP-alkyne, TFP- PEGn-alkyne, TFP-azide, TFP-PEGn-Azide, PTP-DBCO, PTP-PEGn-DBCO, BCN-Endo-PTP, BCN-Endo-PEGn-PTP, PTP-DIBO, PTP-PEGn-DIBO, PTP- DIFO, PTP-PEGn-DIFO, PTP-BCN, PTP-PEGn-BCN, PTP-TCO, PTP-PEGn- TCO, PTP-alkyne, PTP-PEGn-alkyne, PTP-azide, PTP-PEGn-Azide, NPC-DBCO, NPC-PEGn-DBCO, BCN-Endo-NPC, BCN-Endo-PEGn-NPC, NPC-DIBO, NPC- PEGn-DIBO, NPC-DIFO, NPC-PEGn-DIFO, NPC-BCN, NPC-PEGn-BCN, NPC- TCO, NPC-PEGn-TCO, NPC-alkyne, NPC-PEGn-alkyne, NPC-azide, NPC-PEGn- Azide, NCS-azide, NCS-PEGn-azide, NCS-alkyne, NCS-PEGn-alkyne, NCS- DBCO, NCS-PEGn-DBCO, BCN-Endo-NCS, BCN-Endo-PEGn-NCS, NCS-DIBO, NCS-PEGn-DIBO, NCS-DIFO, NCS-PEGn-DIFO, NCS-BCN, NCS-PEGn-BCN, DBCO-COOH, DBCO-PEGn-COOH, BCN-Endo-COOH, BCN-Endo-PEGn- COOH, BCN-COOH, BCN-PEGn-COOH, DIBO-COOH, DIBO-PEGn-COOH, DIFO-COOH, DIFO-PEGn-COOH, Alkyne-COOH, and Alkyne-PEGn-COOH, wherein n represents the number of ethylene glycol repeating units between 2 and 10.

[0193] Preferably, the interconnecting molecule is selected from NHS-PEGn-DBCO, Endo-BCN-PEGn-NHS, NHS-PEGn-DIBO, NHS-PEGn-DIFO, NHS-PEGn-BCN, NHS-DBCO, Amine-PEGn-DBCO, Amine-DBCO,Acid-PEGn-DBCO, Acid-DBCO, STP-PEGn-DBCO, STP-DBCO, TFP-DBCO, TFP-PEGn-DBCO, and PTP-PEGn- DBCO, and PTP-DBCO. More preferably, the interconnecting molecule is selected from NHS-PEGn-DBCO, NHS-azide, and NHS-PEGn-Azide.

[0194] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0195] A) a human serum albumin (HSA);

[0196] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0197] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, and wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an interconnecting molecule selected from NHS-DBCO, NHS-PEGn-DBCO, BCN-Endo-NHS, BCN-Endo-PEGn-NHS, NHS-DIBO, NHS-PEGn-DIBO, NHS-DIFO, NHS-PEGn-DIFO, NHS-BCN, NHS- PEGn-BCN, NHS-TCO, NHS-PEGn-TCO, NHS-alkyne, NHS-PEGn-alkyne, NHS- azide, NHS-PEGn-Azide, STP-DBCO, STP-PEGn-DBCO, BCN-Endo-STP, BCN- Endo-PEGn-STP, STP-DIBO, STP-PEGn-DIBO, STP-DIFO, STP-PEGn-DIFO, STP-BCN, STP-PEGn-BCN, STP-TCO, STP-PEGn-TCO, STP-alkyne, STP- PEGn-alkyne, STP-azide, STP-PEGn-Azide, TFP-DBCO, TFP-PEGn-DBCO, BCN-Endo-TFP, BCN-Endo-PEGn-TFP, TFP-DIBO, TFP-PEGn-DIBO, TFP-DIFO, TFP-PEGn-DIFO, TFP-BCN, TFP-PEGn-BCN, TFP-TCO, TFP-PEGn-TCO, TFP- alkyne, TFP-PEGn-alkyne, TFP-azide, TFP-PEGn-Azide, PTP-DBCO, PTP-PEGn- DBCO, BCN-Endo-PTP, BCN-Endo-PEGn-PTP, PTP-DIBO, PTP-PEGn-DIBO, PTP-DIFO, PTP-PEGn-DIFO, PTP-BCN, PTP-PEGn-BCN, PTP-TCO, PTP-PEGn- TCO, PTP-alkyne, PTP-PEGn-alkyne, PTP-azide, PTP-PEGn-Azide, NPC-DBCO, NPC-PEGn-DBCO, BCN-Endo-NPC, BCN-Endo-PEGn-NPC, NPC-DIBO, NPC- PEGn-DIBO, NPC-DIFO, NPC-PEGn-DIFO, NPC-BCN, NPC-PEGn-BCN, NPC- TCO, NPC-PEGn-TCO, NPC-alkyne, NPC-PEGn-alkyne, NPC-azide, NPC-PEGn- Azide, NCS-azide, NCS-PEGn-azide, NCS-alkyne, NCS-PEGn-alkyne, NCS- DBCO, NCS-PEGn-DBCO, BCN-Endo-NCS, BCN-Endo-PEGn-NCS, NCS-DIBO, NCS-PEGn-DIBO, NCS-DIFO, NCS-PEGn-DIFO, NCS-BCN, NCS-PEGn-BCN, DBCO-COOH, DBCO-PEGn-COOH, BCN-Endo-COOH, BCN-Endo-PEGn- COOH, BCN-COOH, BCN-PEGn-COOH, DIBO-COOH, DIBO-PEGn-COOH, DIFO-COOH, DIFO-PEGn-COOH, Alkyne-COOH, and Alkyne-PEGn-COOH, wherein n represents the number of ethylene glycol repeating units between 2 and 10, and the molar ratio of the interconnecting molecule to HSA is comprised between 3 and 59, and / or wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59.

[0198] In a preferred embodiment, the HSA-nanocamer system for drug delivery, comprises:

[0199] A) a human serum albumin (HSA);

[0200] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0201] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, and wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an interconnecting molecule selected from NHS-DBCO, NHS-PEGn-DBCO, BCN-Endo-NHS, BCN-Endo-PEGn-NHS, NHS-DIBO, NHS-PEGn-DIBO, NHS-DIFO, NHS-PEGn-DIFO, NHS-BCN, NHS- PEGn-BCN, NHS-TCO, NHS-PEGn-TCO, NHS-alkyne, NHS-PEGn-alkyne, NHS- azide, NHS-PEGn-Azide, STP-DBCO, STP-PEGn-DBCO, BCN-Endo-STP, BCN- Endo-PEGn-STP, STP-DIBO, STP-PEGn-DIBO, STP-DIFO, STP-PEGn-DIFO, STP-BCN, STP-PEGn-BCN, STP-TCO, STP-PEGn-TCO, STP-alkyne, STP- PEGn-alkyne, STP-azide, STP-PEGn-Azide, TFP-DBCO, TFP-PEGn-DBCO, BCN-Endo-TFP, BCN-Endo-PEGn-TFP, TFP-DIBO, TFP-PEGn-DIBO, TFP-DIFO, TFP-PEGn-DIFO, TFP-BCN, TFP-PEGn-BCN, TFP-TCO, TFP-PEGn-TCO, TFP- alkyne, TFP-PEGn-alkyne, TFP-azide, TFP-PEGn-Azide, PTP-DBCO, PTP-PEGn- DBCO, BCN-Endo-PTP, BCN-Endo-PEGn-PTP, PTP-DIBO, PTP-PEGn-DIBO, PTP-DIFO, PTP-PEGn-DIFO, PTP-BCN, PTP-PEGn-BCN, PTP-TCO, PTP-PEGn- TCO, PTP-alkyne, PTP-PEGn-alkyne, PTP-azide, PTP-PEGn-Azide, NPC-DBCO, NPC-PEGn-DBCO, BCN-Endo-NPC, BCN-Endo-PEGn-NPC, NPC-DIBO, NPC- PEGn-DIBO, NPC-DIFO, NPC-PEGn-DIFO, NPC-BCN, NPC-PEGn-BCN, NPC- TCO, NPC-PEGn-TCO, NPC-alkyne, NPC-PEGn-alkyne, NPC-azide, NPC-PEGn- Azide, NCS-azide, NCS-PEGn-azide, NCS-alkyne, NCS-PEGn-alkyne, NCS- DBCO, NCS-PEGn-DBCO, BCN-Endo-NCS, BCN-Endo-PEGn-NCS, NCS-DIBO, NCS-PEGn-DIBO, NCS-DIFO, NCS-PEGn-DIFO, NCS-BCN, NCS-PEGn-BCN, DBCO-COOH, DBCO-PEGn-COOH, BCN-Endo-COOH, BCN-Endo-PEGn- COOH, BCN-COOH, BCN-PEGn-COOH, DIBO-COOH, DIBO-PEGn-COOH, DIFO-COOH, DIFO-PEGn-COOH, Alkyne-COOH, and Alkyne-PEGn-COOH, wherein n represents the number of ethylene glycol repeating units between 2 and 10, and the molar ratio of the interconnecting molecule to HSA is comprised between 3 and 59, and wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59

[0202] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0203] A) a human serum albumin (HSA);

[0204] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0205] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an interconnecting molecule selected from NHS- DBCO, NHS-PEGn-DBCO, BCN-Endo-NHS, BCN-Endo-PEGn-NHS, NHS-DIBO, NHS-PEGn-DIBO, NHS-DIFO, NHS-PEGn-DIFO, NHS-BCN, NHS-PEGn-BCN, NHS-TCO, NHS-PEGn-TCO, NHS-alkyne, NHS-PEGn-alkyne, NHS-azide, NHS- PEGn-Azide, STP-DBCO, STP-PEGn-DBCO, BCN-Endo-STP, BCN-Endo-PEGn- STP, STP-DIBO, STP-PEGn-DIBO, STP-DIFO, STP-PEGn-DIFO, STP-BCN, STP-PEGn-BCN, STP-TCO, STP-PEGn-TCO, STP-alkyne, STP-PEGn-alkyne, STP-azide, STP-PEGn-Azide, TFP-DBCO, TFP-PEGn-DBCO, BCN-Endo-TFP, BCN-Endo-PEGn-TFP, TFP-DIBO, TFP-PEGn-DIBO, TFP-DIFO, TFP-PEGn- DIFO, TFP-BCN, TFP-PEGn-BCN, TFP-TCO, TFP-PEGn-TCO, TFP-alkyne, TFP- PEGn-alkyne, TFP-azide, TFP-PEGn-Azide, PTP-DBCO, PTP-PEGn-DBCO, BCN-Endo-PTP, BCN-Endo-PEGn-PTP, PTP-DIBO, PTP-PEGn-DIBO, PTP- DIFO, PTP-PEGn-DIFO, PTP-BCN, PTP-PEGn-BCN, PTP-TCO, PTP-PEGn- TCO, PTP-alkyne, PTP-PEGn-alkyne, PTP-azide, PTP-PEGn-Azide, NPC-DBCO, NPC-PEGn-DBCO, BCN-Endo-NPC, BCN-Endo-PEGn-NPC, NPC-DIBO, NPC- PEGn-DIBO, NPC-DIFO, NPC-PEGn-DIFO, NPC-BCN, NPC-PEGn-BCN, NPC- TCO, NPC-PEGn-TCO, NPC-alkyne, NPC-PEGn-alkyne, NPC-azide, NPC-PEGn- Azide, NCS-azide, NCS-PEGn-azide, NCS-alkyne, NCS-PEGn-alkyne, NCS- DBCO, NCS-PEGn-DBCO, BCN-Endo-NCS, BCN-Endo-PEGn-NCS, NCS-DIBO, NCS-PEGn-DIBO, NCS-DIFO, NCS-PEGn-DIFO, NCS-BCN, NCS-PEGn-BCN, DBCO-COOH, DBCO-PEGn-COOH, BCN-Endo-COOH, BCN-Endo-PEGn- COOH, BCN-COOH, BCN-PEGn-COOH, DIBO-COOH, DIBO-PEGn-COOH, DIFO-COOH, DIFO-PEGn-COOH, Alkyne-COOH, and Alkyne-PEGn-COOH, wherein n represents the number of ethylene glycol repeating units between 2 and 10, and the molar ratio of the interconnecting molecule to HSA is comprised between 3 and 59, wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59, wherein the molar ratio of the immunomodulatory drug to HSA is comprised between 1 and 30, and wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties are selected from the group consisting of ManpNs, ManpsNs, (Manp)3N3, and (Manp3)3N3, preferably ManpsNs.

[0206] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0207] A) a human serum albumin (HSA);

[0208] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0209] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an interconnecting molecule selected from NHS- DBCO, NHS-PEGn-DBCO, BCN-Endo-NHS, BCN-Endo-PEGn-NHS, NHS-DIBO, NHS-PEGn-DIBO, NHS-DIFO, NHS-PEGn-DIFO, NHS-BCN, NHS-PEGn-BCN, NHS-TCO, NHS-PEGn-TCO, NHS-alkyne, NHS-PEGn-alkyne, NHS-azide, NHS- PEGn-Azide, STP-DBCO, STP-PEGn-DBCO, BCN-Endo-STP, BCN-Endo-PEGn- STP, STP-DIBO, STP-PEGn-DIBO, STP-DIFO, STP-PEGn-DIFO, STP-BCN, STP-PEGn-BCN, STP-TCO, STP-PEGn-TCO, STP-alkyne, STP-PEGn-alkyne, STP-azide, STP-PEGn-Azide, TFP-DBCO, TFP-PEGn-DBCO, BCN-Endo-TFP, BCN-Endo-PEGn-TFP, TFP-DIBO, TFP-PEGn-DIBO, TFP-DIFO, TFP-PEGn- DIFO, TFP-BCN, TFP-PEGn-BCN, TFP-TCO, TFP-PEGn-TCO, TFP-alkyne, TFP- PEGn-alkyne, TFP-azide, TFP-PEGn-Azide, PTP-DBCO, PTP-PEGn-DBCO, BCN-Endo-PTP, BCN-Endo-PEGn-PTP, PTP-DIBO, PTP-PEGn-DIBO, PTP- DIFO, PTP-PEGn-DIFO, PTP-BCN, PTP-PEGn-BCN, PTP-TCO, PTP-PEGn- TCO, PTP-alkyne, PTP-PEGn-alkyne, PTP-azide, PTP-PEGn-Azide, NPC-DBCO, NPC-PEGn-DBCO, BCN-Endo-NPC, BCN-Endo-PEGn-NPC, NPC-DIBO, NPC- PEGn-DIBO, NPC-DIFO, NPC-PEGn-DIFO, NPC-BCN, NPC-PEGn-BCN, NPC- TCO, NPC-PEGn-TCO, NPC-alkyne, NPC-PEGn-alkyne, NPC-azide, NPC-PEGn- Azide, NCS-azide, NCS-PEGn-azide, NCS-alkyne, NCS-PEGn-alkyne, NCS- DBCO, NCS-PEGn-DBCO, BCN-Endo-NCS, BCN-Endo-PEGn-NCS, NCS-DIBO, NCS-PEGn-DIBO, NCS-DIFO, NCS-PEGn-DIFO, NCS-BCN, NCS-PEGn-BCN, DBCO-COOH, DBCO-PEGn-COOH, BCN-Endo-COOH, BCN-Endo-PEGn- COOH, BCN-COOH, BCN-PEGn-COOH, DIBO-COOH, DIBO-PEGn-COOH, DIFO-COOH, DIFO-PEGn-COOH, Alkyne-COOH, and Alkyne-PEGn-COOH, wherein n represents the number of ethylene glycol repeating units between 2 and 10, and the molar ratio of the interconnecting molecule to HSA is comprised between 3 and 59, wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59, wherein the molar ratio of the immunomodulatory drug to HSA is comprised between 1 and 30, and wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties are selected from the group consisting of ManpNs, ManpsNs, (Manp)3N3, and (Manp3)3N3, preferably ManpsNs, and wherein the HSA bound to the plurality of mannose moieties and to the at least one immunomodulatory drug is backfolded by a rapid dilution step.

[0210] In another embodiment, the HSA nanocarrier system comprises a plurality of monomannose or dimannose or trimannose moieties covalently bound to the HSA via an NHS-PEGn-DBCO interconnecting molecule. Thus, the present invention is also directed to an HSA-nanocamer system for drug delivery, comprising: A) a human serum albumin (HSA);

[0211] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0212] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an NHS-PEGn-DBCO interconnecting molecule.

[0213] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0214] A) a human serum albumin (HSA);

[0215] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0216] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, and wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an NHS-PEGn-DBCO interconnecting molecule, and the molar ratio of the interconnecting molecule to HSA is comprised between 3 and 59, and / or wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59.

[0217] In a preferred embodiment, the HSA-nanocamer system for drug delivery, comprises:

[0218] A) a human serum albumin (HSA);

[0219] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0220] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, and wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an NHS-PEGn-DBCO interconnecting molecule, and the molar ratio of the interconnecting molecule to HSA is comprised between 3 and 59, and wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59 Preferably, the HSA-nanocarrier system for drug delivery, comprises:

[0221] A) a human serum albumin (HSA);

[0222] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0223] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an NHS-PEGn-DBCO interconnecting molecule, and the molar ratio of the interconnecting molecule to HSA is comprised between 3 and 59, wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59, wherein the molar ratio of the immunomodulatory drug to HSA is comprised between 1 and 30, and wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties are selected from the group consisting of ManpNs, ManpsNs, (Manp)3N3, and (Manp3)3N3, preferably ManpsNs.

[0224] Preferably, the HSA-nanocarrier system for drug delivery, comprises:

[0225] A) a human serum albumin (HSA);

[0226] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0227] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an NHS-PEGn-DBCO interconnecting molecule, and the molar ratio of the interconnecting molecule to HSA is comprised between 3 and 59, wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59, wherein the molar ratio of the immunomodulatory drug to HSA is comprised between 1 and 30, and wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties are selected from the group consisting of ManpNs, ManpsNs, (Manp)3N3, and (Manp3)3N3, preferably ManpsNs, and wherein the HSA bound to the plurality of mannose moieties and to the at least one immunomodulatory drug is backfolded by a rapid dilution step. In preferred embodiments, the at least one immunomodulatory drug is selected from TLR agonist, TLR7 / 8 agonist, PARP inhibitor, JAK inhibitor, STAT3 inhibitor, Cucurbitacin B, ERAP2 inhibitor, IDO1 inhibitor, curcuminoids, gingerol, and silibinin. Thus, the present invention is also directed to an

[0228] HSA-nanocarrier system for drug delivery, wherein said nanocarrier system comprises:

[0229] A) a human serum albumin (HSA);

[0230] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0231] C) at least one immunomodulatory drug covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, and the at least one immunomodulatory drug is selected from TLR agonist, TLR7 / 8 agonist, PARP inhibitor, JAK inhibitor, STAT3 inhibitor, Cucurbitacin B, ERAP2 inhibitor, IDO1 inhibitor, curcuminoids, gingerol, and silibinin.

[0232] In another embodiment, the HSA nanocamer system comprises at least one immunomodulatory drug selected from a TLR7 / 8 agonist or a STAT3 inhibitor. Thus, the present invention is also directed to an HSA-nanocarrier system for drug delivery, comprising:

[0233] A) a human serum albumin (HSA);

[0234] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0235] C) at least one immunomodulatory drug selected from TLR7 / 8 agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering.

[0236] Preferably, the HSA-nanocarrier system for drug delivery, comprises:

[0237] A) a human serum albumin (HSA);

[0238] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0239] C) at least one immunomodulatory drug selected from TLR7 / 8 agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an interconnecting molecule comprising polyethylene glycol with a number of ethylene glycol repeating units between 2 and 10.

[0240] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0241] A) a human serum albumin (HSA);

[0242] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0243] C) at least one immunomodulatory drug selected from TLR7 / 8 agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an NHS-PEGn-DBCO interconnecting molecule.

[0244] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0245] A) a human serum albumin (HSA);

[0246] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0247] C) at least one immunomodulatory drug selected from TLR7 / 8 agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an interconnecting molecule selected from NHS- DBCO, NHS-PEGn-DBCO, BCN-Endo-NHS, BCN-Endo-PEGn-NHS, NHS-DIBO, NHS-PEGn-DIBO, NHS-DIFO, NHS-PEGn-DIFO, NHS-BCN, NHS-PEGn-BCN, NHS-TCO, NHS-PEGn-TCO, NHS-alkyne, NHS-PEGn-alkyne, NHS-azide, NHS- PEGn-Azide, STP-DBCO, STP-PEGn-DBCO, BCN-Endo-STP, BCN-Endo-PEGn- STP, STP-DIBO, STP-PEGn-DIBO, STP-DIFO, STP-PEGn-DIFO, STP-BCN, STP-PEGn-BCN, STP-TCO, STP-PEGn-TCO, STP-alkyne, STP-PEGn-alkyne, STP-azide, STP-PEGn-Azide, TFP-DBCO, TFP-PEGn-DBCO, BCN-Endo-TFP, BCN-Endo-PEGn-TFP, TFP-DIBO, TFP-PEGn-DIBO, TFP-DIFO, TFP-PEGn- DIFO, TFP-BCN, TFP-PEGn-BCN, TFP-TCO, TFP-PEGn-TCO, TFP-alkyne, TFP- PEGn-alkyne, TFP-azide, TFP-PEGn-Azide, PTP-DBCO, PTP-PEGn-DBCO, BCN-Endo-PTP, BCN-Endo-PEGn-PTP, PTP-DIBO, PTP-PEGn-DIBO, PTP- DIFO, PTP-PEGn-DIFO, PTP-BCN, PTP-PEGn-BCN, PTP-TCO, PTP-PEGn- TCO, PTP-alkyne, PTP-PEGn-alkyne, PTP-azide, PTP-PEGn-Azide, NPC-DBCO, NPC-PEGn-DBCO, BCN-Endo-NPC, BCN-Endo-PEGn-NPC, NPC-DIBO, NPC- PEGn-DIBO, NPC-DIFO, NPC-PEGn-DIFO, NPC-BCN, NPC-PEGn-BCN, NPC- TCO, NPC-PEGn-TCO, NPC-alkyne, NPC-PEGn-alkyne, NPC-azide, NPC-PEGn- Azide, NCS-azide, NCS-PEGn-azide, NCS-alkyne, NCS-PEGn-alkyne, NCS- DBCO, NCS-PEGn-DBCO, BCN-Endo-NCS, BCN-Endo-PEGn-NCS, NCS-DIBO, NCS-PEGn-DIBO, NCS-DIFO, NCS-PEGn-DIFO, NCS-BCN, NCS-PEGn-BCN, DBCO-COOH, DBCO-PEGn-COOH, BCN-Endo-COOH, BCN-Endo-PEGn- COOH, BCN-COOH, BCN-PEGn-COOH, DIBO-COOH, DIBO-PEGn-COOH, DIFO-COOH, DIFO-PEGn-COOH, Alkyne-COOH, and Alkyne-PEGn-COOH, wherein n represents the number of ethylene glycol repeating units between 2 and 10.

[0248] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0249] A) a human serum albumin (HSA);

[0250] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0251] C) at least one immunomodulatory drug selected from TLR7 / 8 agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, and wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an NHS-PEGn-DBCO interconnecting molecule, and the molar ratio of the interconnecting molecule to HSA is comprised between 3 and 59, and / or wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59.

[0252] In a preferred embodiment, the HSA-nanocamer system for drug delivery, comprises:

[0253] A) a human serum albumin (HSA);

[0254] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0255] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, and wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an NHS-PEGn-DBCO interconnecting molecule, and the molar ratio of the interconnecting molecule to HSA is comprised between 3 and 59, and wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59

[0256] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0257] A) a human serum albumin (HSA);

[0258] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0259] C) at least one immunomodulatory drug selected from TLR7 / 8 agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an NHS-PEGn-DBCO interconnecting molecule, and the molar ratio of the interconnecting molecule to HSA is comprised between 3 and 59, wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59, wherein the molar ratio of the immunomodulatory drug to HSA is comprised between 1 and 30, and wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties are selected from the group consisting of ManpNs, ManpsNs, (Manp)3N3, and (Manp3)3N3, preferably ManpsNs.

[0260] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0261] A) a human serum albumin (HSA);

[0262] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0263] C) at least one immunomodulatory drug selected from TLR7 / 8 agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an interconnecting molecule comprising polyethylene glycol with a number of ethylene glycol repeating units between 2 and 10, and the molar ratio of the interconnecting molecule to HSA is comprised between 3 and 59, wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59, wherein the molar ratio of the immunomodulatory drug to HSA is comprised between 1 and 30, and wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties are selected from the group consisting of ManpNs, ManpsNs, (Manp)3N3, and (Manps^Ns, preferably ManpsNs, and wherein the HSA bound to the plurality of mannose moieties and to the at least one immunomodulatory drug is backfolded by a rapid dilution step.

[0264] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0265] A) a human serum albumin (HSA);

[0266] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0267] C) at least one immunomodulatory drug selected from TLR7 / 8 agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an NHS-PEGn-DBCO interconnecting molecule, and the molar ratio of the interconnecting molecule to HSA is comprised between 3 and 59, wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59, wherein the molar ratio of the immunomodulatory drug to HSA is comprised between 1 and 30, and wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties are selected from the group consisting of ManpNs, ManpsNs, (Manp)3N3, and (Manps^Ns, preferably ManpsNs, and wherein the HSA bound to the plurality of mannose moieties and to the at least one immunomodulatory drug is backfolded by a rapid dilution step.

[0268] In another embodiment, the HSA nanocamer system comprises at least one immunomodulatory drug selected from a TLR7 / 8 agonist or Cucurbitacin B. Thus, the present invention is also directed to an HSA-nanocamer system for drug delivery, comprising:

[0269] A) a human serum albumin (HSA);

[0270] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0271] C) at least one immunomodulatory drug selected from TLR7 / 8 agonist or Cucurbitacin B covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering.

[0272] Preferably, the HSA-nanocamer system for drug delivery, comprises: A) a human serum albumin (HSA); B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0273] C) at least one immunomodulatory drug selected from TLR7 / 8 agonist or Cucurbitacin B covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an interconnecting molecule comprising polyethylene glycol with a number of ethylene glycol repeating units between 2 and 10.

[0274] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0275] A) a human serum albumin (HSA);

[0276] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0277] C) at least one immunomodulatory drug selected from TLR7 / 8 agonist or Cucurbitacin B covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an NHS-PEGn-DBCO interconnecting molecule.

[0278] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0279] A) a human serum albumin (HSA);

[0280] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0281] C) at least one immunomodulatory drug selected from TLR7 / 8 agonist or Cucurbitacin B covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an interconnecting molecule selected from NHS- DBCO, NHS-PEGn-DBCO, BCN-Endo-NHS, BCN-Endo-PEGn-NHS, NHS-DIBO, NHS-PEGn-DIBO, NHS-DIFO, NHS-PEGn-DIFO, NHS-BCN, NHS-PEGn-BCN, NHS-TCO, NHS-PEGn-TCO, NHS-alkyne, NHS-PEGn-alkyne, NHS-azide, NHS- PEGn-Azide, STP-DBCO, STP-PEGn-DBCO, BCN-Endo-STP, BCN-Endo-PEGn- STP, STP-DIBO, STP-PEGn-DIBO, STP-DIFO, STP-PEGn-DIFO, STP-BCN, STP-PEGn-BCN, STP-TCO, STP-PEGn-TCO, STP-alkyne, STP-PEGn-alkyne, STP-azide, STP-PEGn-Azide, TFP-DBCO, TFP-PEGn-DBCO, BCN-Endo-TFP, BCN-Endo-PEGn-TFP, TFP-DIBO, TFP-PEGn-DIBO, TFP-DIFO, TFP-PEGn- DIFO, TFP-BCN, TFP-PEGn-BCN, TFP-TCO, TFP-PEGn-TCO, TFP-alkyne, TFP- PEGn-alkyne, TFP-azide, TFP-PEGn-Azide, PTP-DBCO, PTP-PEGn-DBCO, BCN-Endo-PTP, BCN-Endo-PEGn-PTP, PTP-DIBO, PTP-PEGn-DIBO, PTP- DIFO, PTP-PEGn-DIFO, PTP-BCN, PTP-PEGn-BCN, PTP-TCO, PTP-PEGn- TCO, PTP-alkyne, PTP-PEGn-alkyne, PTP-azide, PTP-PEGn-Azide, NPC-DBCO, NPC-PEGn-DBCO, BCN-Endo-NPC, BCN-Endo-PEGn-NPC, NPC-DIBO, NPC- PEGn-DIBO, NPC-DIFO, NPC-PEGn-DIFO, NPC-BCN, NPC-PEGn-BCN, NPC- TCO, NPC-PEGn-TCO, NPC-alkyne, NPC-PEGn-alkyne, NPC-azide, NPC-PEGn- Azide, NCS-azide, NCS-PEGn-azide, NCS-alkyne, NCS-PEGn-alkyne, NCS- DBCO, NCS-PEGn-DBCO, BCN-Endo-NCS, BCN-Endo-PEGn-NCS, NCS-DIBO, NCS-PEGn-DIBO, NCS-DIFO, NCS-PEGn-DIFO, NCS-BCN, NCS-PEGn-BCN, DBCO-COOH, DBCO-PEGn-COOH, BCN-Endo-COOH, BCN-Endo-PEGn- COOH, BCN-COOH, BCN-PEGn-COOH, DIBO-COOH, DIBO-PEGn-COOH, DIFO-COOH, DIFO-PEGn-COOH, Alkyne-COOH, and Alkyne-PEGn-COOH, wherein n represents the number of ethylene glycol repeating units between 2 and 10.

[0282] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0283] A) a human serum albumin (HSA);

[0284] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0285] C) at least one immunomodulatory drug selected from TLR7 / 8 agonist or Cucurbitacin B covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, and wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an NHS-PEGn-DBCO interconnecting molecule, and the molar ratio of the interconnecting molecule to HSA is comprised between 3 and 59, and / or wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59.

[0286] In a preferred embodiment, the HSA-nanocamer system for drug delivery, comprises:

[0287] A) a human serum albumin (HSA);

[0288] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA; C) at least one immunomodulatory drug selected from TLR agonist or Cucurbitacin B covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, and wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an NHS-PEGn-DBCO interconnecting molecule, and the molar ratio of the interconnecting molecule to HSA is comprised between 3 and 59, and wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59

[0289] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0290] A) a human serum albumin (HSA);

[0291] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0292] C) at least one immunomodulatory drug selected from TLR7 / 8 agonist or Cucurbitacin B covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an NHS-PEGn-DBCO interconnecting molecule, and the molar ratio of the interconnecting molecule to HSA is comprised between 3 and 59, wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59, wherein the molar ratio of the immunomodulatory drug to HSA is comprised between 1 and 30, and wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties are selected from the group consisting of ManpNs, ManpsNs, (Manp)3N3, and (Manp3)3N3, preferably ManpsNs.

[0293] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0294] A) a human serum albumin (HSA);

[0295] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0296] C) at least one immunomodulatory drug selected from TLR7 / 8 agonist or Cucurbitacin B covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an interconnecting molecule comprising polyethylene glycol with a number of ethylene glycol repeating units between 2 and 10, and the molar ratio of the interconnecting molecule to HSA is comprised between 3 and 59, wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59, wherein the molar ratio of the immunomodulatory drug to HSA is comprised between 1 and 30, and wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties are selected from the group consisting of ManpNs, ManpsNs, (Manp)3N3, and (Manp3)3N3, preferably ManpsNs, and wherein the HSA bound to the plurality of mannose moieties and to the at least one immunomodulatory drug is backfolded by a rapid dilution step.

[0297] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0298] A) a human serum albumin (HSA);

[0299] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0300] C) at least one immunomodulatory drug selected from TLR7 / 8 agonist or Cucurbitacin B covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an NHS-PEGn-DBCO interconnecting molecule, and the molar ratio of the interconnecting molecule to HSA is comprised between 3 and 59, wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59, wherein the molar ratio of the immunomodulatory drug to HSA is comprised between 1 and 30, and wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties are selected from the group consisting of ManpNs, ManpsNs, (Manp)3N3, and (Manp3)3N3, preferably ManpsNs, and wherein the HSA bound to the plurality of mannose moieties and to the at least one immunomodulatory drug is backfolded by a rapid dilution step.

[0301] In another embodiment, the HSA nanocarrier system comprises a TLR7 / 8 agonist as immunomodulatory drug. Thus, the present invention is also directed to an HSA-nanocamer system for drug delivery, comprising:

[0302] A) a human serum albumin (HSA);

[0303] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0304] C) a TLR7 / 8 agonist as immunomodulatory drug covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering.

[0305] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0306] A) a human serum albumin (HSA);

[0307] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0308] C) a TLR7 / 8 agonist as immunomodulatory drug covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an interconnecting molecule comprising polyethylene glycol with a number of ethylene glycol repeating units between 2 and 10.

[0309] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0310] A) a human serum albumin (HSA);

[0311] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0312] C) a TLR7 / 8 agonist as immunomodulatory drug covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an NHS-PEGn-DBCO interconnecting molecule.

[0313] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0314] A) a human serum albumin (HSA);

[0315] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0316] C) a TLR7 / 8 agonist as immunomodulatory drug covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an interconnecting molecule selected from NHS- DBCO, NHS-PEGn-DBCO, BCN-Endo-NHS, BCN-Endo-PEGn-NHS, NHS-DIBO, NHS-PEGn-DIBO, NHS-DIFO, NHS-PEGn-DIFO, NHS-BCN, NHS-PEGn-BCN, NHS-TCO, NHS-PEGn-TCO, NHS-alkyne, NHS-PEGn-alkyne, NHS-azide, NHS- PEGn-Azide, STP-DBCO, STP-PEGn-DBCO, BCN-Endo-STP, BCN-Endo-PEGn- STP, STP-DIBO, STP-PEGn-DIBO, STP-DIFO, STP-PEGn-DIFO, STP-BCN, STP-PEGn-BCN, STP-TCO, STP-PEGn-TCO, STP-alkyne, STP-PEGn-alkyne, STP-azide, STP-PEGn-Azide, TFP-DBCO, TFP-PEGn-DBCO, BCN-Endo-TFP, BCN-Endo-PEGn-TFP, TFP-DIBO, TFP-PEGn-DIBO, TFP-DIFO, TFP-PEGn- DIFO, TFP-BCN, TFP-PEGn-BCN, TFP-TCO, TFP-PEGn-TCO, TFP-alkyne, TFP- PEGn-alkyne, TFP-azide, TFP-PEGn-Azide, PTP-DBCO, PTP-PEGn-DBCO, BCN-Endo-PTP, BCN-Endo-PEGn-PTP, PTP-DIBO, PTP-PEGn-DIBO, PTP- DIFO, PTP-PEGn-DIFO, PTP-BCN, PTP-PEGn-BCN, PTP-TCO, PTP-PEGn- TCO, PTP-alkyne, PTP-PEGn-alkyne, PTP-azide, PTP-PEGn-Azide, NPC-DBCO, NPC-PEGn-DBCO, BCN-Endo-NPC, BCN-Endo-PEGn-NPC, NPC-DIBO, NPC- PEGn-DIBO, NPC-DIFO, NPC-PEGn-DIFO, NPC-BCN, NPC-PEGn-BCN, NPC- TCO, NPC-PEGn-TCO, NPC-alkyne, NPC-PEGn-alkyne, NPC-azide, NPC-PEGn- Azide, NCS-azide, NCS-PEGn-azide, NCS-alkyne, NCS-PEGn-alkyne, NCS- DBCO, NCS-PEGn-DBCO, BCN-Endo-NCS, BCN-Endo-PEGn-NCS, NCS-DIBO, NCS-PEGn-DIBO, NCS-DIFO, NCS-PEGn-DIFO, NCS-BCN, NCS-PEGn-BCN, DBCO-COOH, DBCO-PEGn-COOH, BCN-Endo-COOH, BCN-Endo-PEGn- COOH, BCN-COOH, BCN-PEGn-COOH, DIBO-COOH, DIBO-PEGn-COOH, DIFO-COOH, DIFO-PEGn-COOH, Alkyne-COOH, and Alkyne-PEGn-COOH, wherein n represents the number of ethylene glycol repeating units between 2 and 10.

[0317] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0318] A) a human serum albumin (HSA);

[0319] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0320] C) a TLR7 / 8 agonist as immunomodulatory drug covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, and wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an NHS-PEGn-DBCO interconnecting molecule, and the molar ratio of the interconnecting molecule to HSA is comprised between 3 and 59, and / or wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59.

[0321] In a preferred embodiment, the HSA-nanocamer system for drug delivery, comprises:

[0322] A) a human serum albumin (HSA); B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0323] C) a TLR7 / 8 agonist as immunomodulatory drug covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, and wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an NHS-PEGn-DBCO interconnecting molecule, and the molar ratio of the interconnecting molecule to HSA is comprised between 3 and 59, and wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59

[0324] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0325] A) a human serum albumin (HSA);

[0326] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0327] C) a TLR7 / 8 agonist as immunomodulatory drug covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an NHS-PEGn-DBCO interconnecting molecule, and the molar ratio of the interconnecting molecule to HSA is comprised between 3 and 59, wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59, wherein the molar ratio of the immunomodulatory drug to HSA is comprised between 1 and 30, and wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties are selected from the group consisting of ManpNs, ManpsNs, (Manp)3N3, and (Manp3)3N3, preferably ManpsNs.

[0328] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0329] A) a human serum albumin (HSA);

[0330] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0331] C) a TLR7 / 8 agonist as immunomodulatory drug covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an interconnecting molecule comprising polyethylene glycol with a number of ethylene glycol repeating units between 2 and 10, and the molar ratio of the interconnecting molecule to HSA is comprised between 3 and 59, wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59, wherein the molar ratio of the immunomodulatory drug to HSA is comprised between 1 and 30, and wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties are selected from the group consisting of ManpNs, ManpsNs, (Manp)3N3, and (Manp3)3N3, preferably ManpsNs, and wherein the HSA bound to the plurality of mannose moieties and to the at least one immunomodulatory drug is backfolded by a rapid dilution step.

[0332] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0333] A) a human serum albumin (HSA);

[0334] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0335] C) a TLR7 / 8 agonist as immunomodulatory drug covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an NHS-PEGn-DBCO interconnecting molecule, and the molar ratio of the interconnecting molecule to HSA is comprised between 3 and 59, wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59, wherein the molar ratio of the immunomodulatory drug to HSA is comprised between 1 and 30, and wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties are selected from the group consisting of ManpNs, ManpsNs, (Manp)3N3, and (Manp3)3N3, preferably ManpsNs, and wherein the HSA bound to the plurality of mannose moieties and to the at least one immunomodulatory drug is backfolded by a rapid dilution step.

[0336] In another embodiment, the HSA nanocamer system comprises at least one immunomodulatory drug covalently bound to said HSA via a drug linker using a thiol-reactive functional group selected from the group consisting of maleimide, iodoacetamide, and iodoacetate. Thus, the present invention is also directed to an HSA-nanocamer system for drug delivery, comprising:

[0337] A) a human serum albumin (HSA);

[0338] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA; C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, and wherein the immunomodulatory drug is covalently bound to said HSA via a drug linker using a thiol-reactive functional group selected from the group consisting of maleimide, iodoacetamide, and iodoacetate.

[0339] Preferably, the HSA nanocarrier system comprises at least one immunomodulatory drug covalently bound to said HSA via a cleavable drug linker using a thiol-reactive functional group selected from the group consisting of maleimide, iodoacetamide, and iodoacetate. Thus, the present invention is also directed to an HSA-nanocamer system for drug delivery, comprising:

[0340] A) a human serum albumin (HSA);

[0341] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0342] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, and wherein the immunomodulatory drug is covalently bound to said HSA via a cleavable drug linker using a thiol-reactive functional group selected from the group consisting of maleimide, iodoacetamide, and iodoacetate.

[0343] Preferably, the HSA nanocarrier system comprises at least one immunomodulatory drug covalently bound to said HSA via a non-cleavable drug linker using a thiol-reactive functional group selected from the group consisting of maleimide, iodoacetamide, and iodoacetate. Thus, the present invention is also directed to an HSA-nanocamer system for drug delivery, comprising:

[0344] A) a human serum albumin (HSA);

[0345] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0346] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, and wherein the immunomodulatory drug is covalently bound to said HSA via a non-cleavable drug linker using a thiol-reactive functional group selected from the group consisting of maleimide, iodoacetamide, and iodoacetate.

[0347] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0348] A) a human serum albumin (HSA);

[0349] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0350] C) at least one immunomodulatory drug selected from TLR7 / 8 agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, and wherein the immunomodulatory drug is covalently bound to said HSA via a drug linker using a thiol-reactive functional group selected from the group consisting of maleimide, iodoacetamide, and iodoacetate.

[0351] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0352] A) a human serum albumin (HSA);

[0353] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0354] C) at least one immunomodulatory drug selected from TLR7 / 8 agonist or Cucurbitacin B covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, and wherein the immunomodulatory drug is covalently bound to said HSA via a drug linker using a thiol-reactive functional group selected from the group consisting of maleimide, iodoacetamide, and iodoacetate.

[0355] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0356] A) a human serum albumin (HSA);

[0357] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0358] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an interconnecting molecule comprising polyethylene glycol with a number of ethylene glycol repeating units between 2 and 10, and wherein the immunomodulatory drug is covalently bound to said HSA via a drug linker using a thiol-reactive functional group selected from the group consisting of maleimide, iodoacetamide, and iodoacetate.

[0359] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0360] A) a human serum albumin (HSA);

[0361] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0362] C) at least one immunomodulatory drug selected from TLR7 / 8 agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an NHS-PEGn-DBCO interconnecting molecule, and wherein the immunomodulatory drug is covalently bound to said HSA via a drug linker using a thiol-reactive functional group selected from the group consisting of maleimide, iodoacetamide, and iodoacetate.

[0363] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0364] A) a human serum albumin (HSA);

[0365] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0366] C) at least one immunomodulatory drug selected from TLR7 / 8 agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an interconnecting molecule selected from NHS- DBCO, NHS-PEGn-DBCO, BCN-Endo-NHS, BCN-Endo-PEGn-NHS, NHS-DIBO, NHS-PEGn-DIBO, NHS-DIFO, NHS-PEGn-DIFO, NHS-BCN, NHS-PEGn-BCN, NHS-TCO, NHS-PEGn-TCO, NHS-alkyne, NHS-PEGn-alkyne, NHS-azide, NHS- PEGn-Azide, STP-DBCO, STP-PEGn-DBCO, BCN-Endo-STP, BCN-Endo-PEGn- STP, STP-DIBO, STP-PEGn-DIBO, STP-DIFO, STP-PEGn-DIFO, STP-BCN, STP-PEGn-BCN, STP-TCO, STP-PEGn-TCO, STP-alkyne, STP-PEGn-alkyne, STP-azide, STP-PEGn-Azide, TFP-DBCO, TFP-PEGn-DBCO, BCN-Endo-TFP, BCN-Endo-PEGn-TFP, TFP-DIBO, TFP-PEGn-DIBO, TFP-DIFO, TFP-PEGn- DIFO, TFP-BCN, TFP-PEGn-BCN, TFP-TCO, TFP-PEGn-TCO, TFP-alkyne, TFP- PEGn-alkyne, TFP-azide, TFP-PEGn-Azide, PTP-DBCO, PTP-PEGn-DBCO, BCN-Endo-PTP, BCN-Endo-PEGn-PTP, PTP-DIBO, PTP-PEGn-DIBO, PTP- DIFO, PTP-PEGn-DIFO, PTP-BCN, PTP-PEGn-BCN, PTP-TCO, PTP-PEGn- TCO, PTP-alkyne, PTP-PEGn-alkyne, PTP-azide, PTP-PEGn-Azide, NPC-DBCO, NPC-PEGn-DBCO, BCN-Endo-NPC, BCN-Endo-PEGn-NPC, NPC-DIBO, NPC- PEGn-DIBO, NPC-DIFO, NPC-PEGn-DIFO, NPC-BCN, NPC-PEGn-BCN, NPC- TCO, NPC-PEGn-TCO, NPC-alkyne, NPC-PEGn-alkyne, NPC-azide, NPC-PEGn- Azide, NCS-azide, NCS-PEGn-azide, NCS-alkyne, NCS-PEGn-alkyne, NCS- DBCO, NCS-PEGn-DBCO, BCN-Endo-NCS, BCN-Endo-PEGn-NCS, NCS-DIBO, NCS-PEGn-DIBO, NCS-DIFO, NCS-PEGn-DIFO, NCS-BCN, NCS-PEGn-BCN, DBCO-COOH, DBCO-PEGn-COOH, BCN-Endo-COOH, BCN-Endo-PEGn- COOH, BCN-COOH, BCN-PEGn-COOH, DIBO-COOH, DIBO-PEGn-COOH, DIFO-COOH, DIFO-PEGn-COOH, Alkyne-COOH, and Alkyne-PEGn-COOH, wherein n represents the number of ethylene glycol repeating units between 2 and 10, and wherein the immunomodulatory drug is covalently bound to said HSA via a drug linker using a thiol-reactive functional group selected from the group consisting of maleimide, iodoacetamide, and iodoacetate.

[0367] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0368] A) a human serum albumin (HSA);

[0369] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0370] C) at least one immunomodulatory drug selected from TLR7 / 8 agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, and wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an NHS-PEGn-DBCO interconnecting molecule, and the molar ratio of the interconnecting molecule to HSA is comprised between 3 and 59, and / or wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59, and wherein the immunomodulatory drug is covalently bound to said HSA via a drug linker using a thiol-reactive functional group selected from the group consisting of maleimide, iodoacetamide, and iodoacetate.

[0371] In a preferred embodiment, the HSA-nanocamer system for drug delivery, comprises:

[0372] A) a human serum albumin (HSA); B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0373] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, and wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an NHS-PEGn-DBCO interconnecting molecule, and the molar ratio of the interconnecting molecule to HSA is comprised between 3 and 59, and wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59, and wherein the immunomodulatory drug is covalently bound to said HSA via a drug linker using a thiol-reactive functional group selected from the group consisting of maleimide, iodoacetamide, and iodoacetate.

[0374] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0375] A) a human serum albumin (HSA);

[0376] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0377] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an NHS-PEGn-DBCO interconnecting molecule, and the molar ratio of the interconnecting molecule to HSA is comprised between 3 and 59, wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59, wherein the molar ratio of the immunomodulatory drug to HSA is comprised between 1 and 30, and wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties are selected from the group consisting of ManpNs, ManpsNs, (Manp)3N3, and (Manp3)3N3, preferably ManpsNs, and wherein the immunomodulatory drug is covalently bound to said HSA via a drug linker using a thiol-reactive functional group selected from the group consisting of maleimide, iodoacetamide, and iodoacetate.

[0378] Preferably, the HSA-nanocamer system for drug delivery, comprises: A) a human serum albumin (HSA); B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0379] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an interconnecting molecule comprising polyethylene glycol with a number of ethylene glycol repeating units between 2 and 10, and the molar ratio of the interconnecting molecule to HSA is comprised between 3 and 59, wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59, wherein the molar ratio of the immunomodulatory drug to HSA is comprised between 1 and 30, and wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties are selected from the group consisting of ManpNs, ManpsNs, (Manp)3N3, and (Manp3)3N3, preferably ManpsNs, and wherein the HSA bound to the plurality of mannose moieties and to the at least one immunomodulatory drug is backfolded by a rapid dilution step, and wherein the immunomodulatory drug is covalently bound to said HSA via a drug linker using a thiol-reactive functional group selected from the group consisting of maleimide, iodoacetamide, and iodoacetate.

[0380] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0381] A) a human serum albumin (HSA);

[0382] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0383] C) at least one immunomodulatory drug selected from TLR agonist or Cucurbitacin B covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an NHS-PEGn-DBCO interconnecting molecule, and the molar ratio of the interconnecting molecule to HSA is comprised between 3 and 59, wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59, wherein the molar ratio of the immunomodulatory drug to HSA is comprised between 1 and 30, and wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties are selected from the group consisting of ManpNs, ManpsNs, (Manp)3N3, and (Manp3)3N3, preferably ManpsNs, and wherein the HSA bound to the plurality of mannose moieties and to the at least one immunomodulatory drug is backfolded by a rapid dilution step, and wherein the immunomodulatory drug is covalently bound to said HSA via a drug linker using a thiol-reactive functional group selected from the group consisting of maleimide, iodoacetamide, and iodoacetate.

[0384] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0385] A) a human serum albumin (HSA);

[0386] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0387] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an NHS-PEGn-DBCO interconnecting molecule, and the molar ratio of the interconnecting molecule to HSA is comprised between 3 and 59, wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59, wherein the molar ratio of the immunomodulatory drug to HSA is comprised between 1 and 30, and wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties are selected from the group consisting of ManpNs, ManpsNs, (Manp)3N3, and (Manp3)3N3, preferably ManpsNs, and wherein the HSA bound to the plurality of mannose moieties and to the at least one immunomodulatory drug is backfolded by a rapid dilution step, and wherein the immunomodulatory drug is covalently bound to said HSA via a drug linker using a thiol-reactive functional group selected from the group consisting of maleimide, iodoacetamide, and iodoacetate.

[0388] In another embodiment, the HSA nanocamer system comprises at least one immunomodulatory drug covalently bound to said HSA via a drug linker selected from pyridinyldithio ethyl carbonate, pyridinyldithio-propionyl-hydrazide, pyridyldithio-ethylamine, SPDP, SPP, SPDB, pyridyldithio-PEGn-NHS, DMAC- SPDP, DMAC-SPP, pyridinyldithio-PEGn-carboxylic acid, PDB-PFP, PDEC-NB, PPC-NB, maleimide-carboxylic acid, maleimide-amide-PEGn-va-PABC-PNP, maleimide-PEGn-vc-PABC-PNP, mc-vc-PABC-PNP, mc-Val-Cit-PAB-CI, mcc-vc- PAPC-PNP, mcc-PEGn-PABC, mc-va linker, mcc-va linker, mc-va-nhs linker, mcc- va-nhs linker, mc-Gly-Gly-Phe-Gly-PABC, maleimide-hydrazide, vinylsulfone- carbonate, thiosulfonate linker, hydrazide-maleimide linker, iodoacetamide linker, and methanethiosulfonate linker. Thus, the present invention is also directed to an HSA-nanocamer system for drug delivery, comprises:

[0389] A) a human serum albumin (HSA);

[0390] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0391] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, and wherein the immunomodulatory drug is covalently bound to said HSA via a drug linker selected from pyridinyldithio ethyl carbonate, pyridinyldithio-propionyl-hydrazide, pyridyldithio-ethylamine, SPDP, SPP, SPDB, pyridyldithio-PEGn-NHS, DMAC- SPDP, DMAC-SPP, pyridinyldithio-PEGn-carboxylic acid, PDB-PFP, PDEC-NB, PPC-NB, maleimide-carboxylic acid, maleimide-amide-PEGn-va-PABC-PNP, maleimide-PEGn-vc-PABC-PNP, mc-vc-PABC-PNP, mc-Val-Cit-PAB-CI, mcc-vc- PAPC-PNP, mcc-PEGn-PABC, mc-va linker, mcc-va linker, mc-va-nhs linker, mcc- va-nhs linker, mc-Gly-Gly-Phe-Gly-PABC, maleimide-hydrazide, vinylsulfone- carbonate, thiosulfonate linker, hydrazide-maleimide linker, iodoacetamide linker, and methanethiosulfonate linker.

[0392] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0393] A) a human serum albumin (HSA);

[0394] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0395] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, and wherein the immunomodulatory drug is covalently bound to said HSA via a drug linker comprising a thiol-reactive functional group selected from selected from pyridinyldithio-ethoxy-carbonyl-group, maleimide, mc-vc-pabc linker (maleimidocaproyl (me) - valine-citrulline (vc) -para-amino benzyloxycarbonyl (PABC)), thiosulfonate linker, hydrazide-maleimide linker, iodoacetamide linker, and methanethiosulfonate linker.

[0396] Preferably, the HSA-nanocamer system for drug delivery, comprises: A) a human serum albumin (HSA); B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0397] C) at least one immunomodulatory drug selected from TLR7 / 8 agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, and wherein the immunomodulatory drug is covalently bound to said HSA via a drug linker selected from pyridinyldithio ethyl carbonate, pyridinyldithio-propionyl-hydrazide, pyridyldithio-ethylamine, SPDP, SPP, SPDB, pyridyldithio-PEGn-NHS, DMAC- SPDP, DMAC-SPP, pyridinyldithio-PEGn-carboxylic acid, PDB-PFP, PDEC-NB, PPC-NB, maleimide-carboxylic acid, maleimide-amide-PEGn-va-PABC-PNP, maleimide-PEGn-vc-PABC-PNP, mc-vc-PABC-PNP, mc-Val-Cit-PAB-CI, mcc-vc- PAPC-PNP, mcc-PEGn-PABC, mc-va linker, mcc-va linker, mc-va-nhs linker, mcc- va-nhs linker, mc-Gly-Gly-Phe-Gly-PABC, maleimide-hydrazide, vinylsulfone- carbonate, thiosulfonate linker, hydrazide-maleimide linker, iodoacetamide linker, and methanethiosulfonate linker.

[0398] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0399] A) a human serum albumin (HSA);

[0400] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0401] C) at least one immunomodulatory drug selected from TLR7 / 8 agonist or Cucurbitacin B covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, and wherein the immunomodulatory drug is covalently bound to said HSA via a drug linker selected from pyridinyldithio ethyl carbonate, pyridinyldithio-propionyl-hydrazide, pyridyldithio-ethylamine, SPDP, SPP, SPDB, pyridyldithio-PEGn-NHS, DMAC- SPDP, DMAC-SPP, pyridinyldithio-PEGn-carboxylic acid, PDB-PFP, PDEC-NB, PPC-NB, maleimide-carboxylic acid, maleimide-amide-PEGn-va-PABC-PNP, maleimide-PEGn-vc-PABC-PNP, mc-vc-PABC-PNP, mc-Val-Cit-PAB-CI, mcc-vc- PAPC-PNP, mcc-PEGn-PABC, mc-va linker, mcc-va linker, mc-va-nhs linker, mcc- va-nhs linker, mc-Gly-Gly-Phe-Gly-PABC, maleimide-hydrazide, vinylsulfone- carbonate, thiosulfonate linker, hydrazide-maleimide linker, iodoacetamide linker, and methanethiosulfonate linker.

[0402] Preferably, the HSA-nanocamer system for drug delivery, comprises: A) a human serum albumin (HSA); B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0403] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an interconnecting molecule comprising polyethylene glycol with a number of ethylene glycol repeating units between 2 and 10, and wherein the immunomodulatory drug is covalently bound to said HSA via a drug linker selected from pyridinyldithio ethyl carbonate, pyridinyldithio- propionyl-hydrazide, pyridyldithio-ethylamine, SPDP, SPP, SPDB, pyridyldithio- PEGn-NHS, DMAC-SPDP, DMAC-SPP, pyridinyldithio-PEGn-carboxylic acid, PDB-PFP, PDEC-NB, PPC-NB, maleim ide-carboxylic acid, maleimide-amide- PEGn-va-PABC-PNP, maleimide-PEGn-vc-PABC-PNP, mc-vc-PABC-PNP, mc- Val-Cit-PAB-CI, mcc-vc-PAPC-PNP, mcc-PEGn-PABC, mc-va linker, mcc-va linker, mc-va-nhs linker, mcc-va-nhs linker, mc-Gly-Gly-Phe-Gly-PABC, maleim ide-hydrazide, vinylsulfone-carbonate, thiosulfonate linker, hydrazide- maleimide linker, iodoacetamide linker, and methanethiosulfonate linker.

[0404] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0405] A) a human serum albumin (HSA);

[0406] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0407] C) at least one immunomodulatory drug selected from TLR7 / 8 agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an NHS-PEGn-DBCO interconnecting molecule, and wherein the immunomodulatory drug is covalently bound to said HSA via a drug linker selected from pyridinyldithio ethyl carbonate, pyridinyldithio-propionyl- hydrazide, pyridyldithio-ethylamine, SPDP, SPP, SPDB, pyridyldithio-PEGn-NHS, DMAC-SPDP, DMAC-SPP, pyridinyldithio-PEGn-carboxylic acid, PDB-PFP, PDEC-NB, PPC-NB, maleim ide-carboxylic acid, maleimide-amide-PEGn-va- PABC-PNP, maleimide-PEGn-vc-PABC-PNP, mc-vc-PABC-PNP, mc-Val-Cit-PAB- Cl, mcc-vc-PAPC-PNP, mcc-PEGn-PABC, mc-va linker, mcc-va linker, mc-va-nhs linker, mcc-va-nhs linker, mc-Gly-Gly-Phe-Gly-PABC, maleimide-hydrazide, vinylsulfone-carbonate, thiosulfonate linker, hydrazide-maleimide linker, iodoacetamide linker, and methanethiosulfonate linker.

[0408] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0409] A) a human serum albumin (HSA);

[0410] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0411] C) at least one immunomodulatory drug selected from TLR7 / 8 agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an interconnecting molecule selected from NHS- DBCO, NHS-PEGn-DBCO, BCN-Endo-NHS, BCN-Endo-PEGn-NHS, NHS-DIBO, NHS-PEGn-DIBO, NHS-DIFO, NHS-PEGn-DIFO, NHS-BCN, NHS-PEGn-BCN, NHS-TCO, NHS-PEGn-TCO, NHS-alkyne, NHS-PEGn-alkyne, NHS-azide, NHS- PEGn-Azide, STP-DBCO, STP-PEGn-DBCO, BCN-Endo-STP, BCN-Endo-PEGn- STP, STP-DIBO, STP-PEGn-DIBO, STP-DIFO, STP-PEGn-DIFO, STP-BCN, STP-PEGn-BCN, STP-TCO, STP-PEGn-TCO, STP-alkyne, STP-PEGn-alkyne, STP-azide, STP-PEGn-Azide, TFP-DBCO, TFP-PEGn-DBCO, BCN-Endo-TFP, BCN-Endo-PEGn-TFP, TFP-DIBO, TFP-PEGn-DIBO, TFP-DIFO, TFP-PEGn- DIFO, TFP-BCN, TFP-PEGn-BCN, TFP-TCO, TFP-PEGn-TCO, TFP-alkyne, TFP- PEGn-alkyne, TFP-azide, TFP-PEGn-Azide, PTP-DBCO, PTP-PEGn-DBCO, BCN-Endo-PTP, BCN-Endo-PEGn-PTP, PTP-DIBO, PTP-PEGn-DIBO, PTP- DIFO, PTP-PEGn-DIFO, PTP-BCN, PTP-PEGn-BCN, PTP-TCO, PTP-PEGn- TCO, PTP-alkyne, PTP-PEGn-alkyne, PTP-azide, PTP-PEGn-Azide, NPC-DBCO, NPC-PEGn-DBCO, BCN-Endo-NPC, BCN-Endo-PEGn-NPC, NPC-DIBO, NPC- PEGn-DIBO, NPC-DIFO, NPC-PEGn-DIFO, NPC-BCN, NPC-PEGn-BCN, NPC- TCO, NPC-PEGn-TCO, NPC-alkyne, NPC-PEGn-alkyne, NPC-azide, NPC-PEGn- Azide, NCS-azide, NCS-PEGn-azide, NCS-alkyne, NCS-PEGn-alkyne, NCS- DBCO, NCS-PEGn-DBCO, BCN-Endo-NCS, BCN-Endo-PEGn-NCS, NCS-DIBO, NCS-PEGn-DIBO, NCS-DIFO, NCS-PEGn-DIFO, NCS-BCN, NCS-PEGn-BCN, DBCO-COOH, DBCO-PEGn-COOH, BCN-Endo-COOH, BCN-Endo-PEGn- COOH, BCN-COOH, BCN-PEGn-COOH, DIBO-COOH, DIBO-PEGn-COOH, DIFO-COOH, DIFO-PEGn-COOH, Alkyne-COOH, and Alkyne-PEGn-COOH, wherein n represents the number of ethylene glycol repeating units between 2 and 10, and wherein the immunomodulatory drug is covalently bound to said HSA via a drug linker selected from pyridinyldithio ethyl carbonate, pyridinyldithio-propionyl- hydrazide, pyridyldithio-ethylamine, SPDP, SPP, SPDB, pyridyldithio-PEGn-NHS, DMAC-SPDP, DMAC-SPP, pyridinyldithio-PEGn-carboxylic acid, PDB-PFP, PDEC-NB, PPC-NB, maleim ide-carboxylic acid, maleimide-amide-PEGn-va- PABC-PNP, maleimide-PEGn-vc-PABC-PNP, mc-vc-PABC-PNP, mc-Val-Cit-PAB- Cl, mcc-vc-PAPC-PNP, mcc-PEGn-PABC, mc-va linker, mcc-va linker, mc-va-nhs linker, mcc-va-nhs linker, mc-Gly-Gly-Phe-Gly-PABC, maleimide-hydrazide, vinylsulfone-carbonate, thiosulfonate linker, hydrazide-maleimide linker, iodoacetamide linker, and methanethiosulfonate linker.

[0412] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0413] A) a human serum albumin (HSA);

[0414] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0415] C) at least one immunomodulatory drug selected from TLR7 / 8 agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, and wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an NHS-PEGn-DBCO interconnecting molecule, and the molar ratio of the interconnecting molecule to HSA is comprised between 3 and 59, and / or wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59, and wherein the immunomodulatory drug is covalently bound to said HSA via a drug linker selected from pyridinyldithio ethyl carbonate, pyridinyldithio-propionyl-hydrazide, pyridyldithio-ethylamine, SPDP, SPP, SPDB, pyridyldithio-PEGn-NHS, DMAC- SPDP, DMAC-SPP, pyridinyldithio-PEGn-carboxylic acid, PDB-PFP, PDEC-NB, PPC-NB, maleimide-carboxylic acid, maleimide-amide-PEGn-va-PABC-PNP, maleimide-PEGn-vc-PABC-PNP, mc-vc-PABC-PNP, mc-Val-Cit-PAB-CI, mcc-vc- PAPC-PNP, mcc-PEGn-PABC, mc-va linker, mcc-va linker, mc-va-nhs linker, mcc- va-nhs linker, mc-Gly-Gly-Phe-Gly-PABC, maleimide-hydrazide, vinylsulfone- carbonate, thiosulfonate linker, hydrazide-maleimide linker, iodoacetamide linker, and methanethiosulfonate linker.

[0416] In a preferred embodiment, the HSA-nanocamer system for drug delivery, comprises:

[0417] A) a human serum albumin (HSA);

[0418] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA; C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, and wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an NHS-PEGn-DBCO interconnecting molecule, and the molar ratio of the interconnecting molecule to HSA is comprised between 3 and 59, and wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59, and wherein the immunomodulatory drug is covalently bound to said HSA via a drug linker selected from pyridinyldithio ethyl carbonate, pyridinyldithio-propionyl-hydrazide, pyridyldithio-ethylamine, SPDP, SPP, SPDB, pyridyldithio-PEGn-NHS, DMAC- SPDP, DMAC-SPP, pyridinyldithio-PEGn-carboxylic acid, PDB-PFP, PDEC-NB, PPC-NB, maleimide-carboxylic acid, maleimide-amide-PEGn-va-PABC-PNP, maleimide-PEGn-vc-PABC-PNP, mc-vc-PABC-PNP, mc-Val-Cit-PAB-CI, mcc-vc- PAPC-PNP, mcc-PEGn-PABC, mc-va linker, mcc-va linker, mc-va-nhs linker, mcc- va-nhs linker, mc-Gly-Gly-Phe-Gly-PABC, maleimide-hydrazide, vinylsulfone- carbonate, thiosulfonate linker, hydrazide-maleimide linker, iodoacetamide linker, and methanethiosulfonate linker.

[0419] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0420] A) a human serum albumin (HSA);

[0421] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0422] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an NHS-PEGn-DBCO interconnecting molecule, and the molar ratio of the interconnecting molecule to HSA is comprised between 3 and 59, wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59, wherein the molar ratio of the immunomodulatory drug to HSA is comprised between 1 and 30, and wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties are selected from the group consisting of ManpNs, ManpsNs, (Manp)3N3, and (Manp3)3N3, preferably ManpsNs, and wherein the immunomodulatory drug is covalently bound to said HSA via a drug linker selected from pyridinyldithio ethyl carbonate, pyridinyldithio-propionyl-hydrazide, pyridyldithio-ethylamine, SPDP, SPP, SPDB, pyridyldithio-PEGn-NHS, DMAC-SPDP, DMAC-SPP, pyridinyldithio-PEGn- carboxylic acid, PDB-PFP, PDEC-NB, PPC-NB, maleim ide-carboxylic acid, maleimide-amide-PEGn-va-PABC-PNP, maleimide-PEGn-vc-PABC-PNP, mc-vc- PABC-PNP, mc-Val-Cit-PAB-CI, mcc-vc-PAPC-PNP, mcc-PEGn-PABC, mc-va linker, mcc-va linker, mc-va-nhs linker, mcc-va-nhs linker, mc-Gly-Gly-Phe-Gly- PABC, maleim ide-hydrazide, vinylsulfone-carbonate, thiosulfonate linker, hydrazide-maleimide linker, iodoacetamide linker, and methanethiosulfonate linker.

[0423] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0424] A) a human serum albumin (HSA);

[0425] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0426] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an interconnecting molecule comprising polyethylene glycol with a number of ethylene glycol repeating units between 2 and 10, and the molar ratio of the interconnecting molecule to HSA is comprised between 3 and 59, wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59, wherein the molar ratio of the immunomodulatory drug to HSA is comprised between 1 and 30, and wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties are selected from the group consisting of ManpNs, ManpsNs, (Manp)3N3, and (Manp3)3N3, preferably ManpsNs, and wherein the HSA bound to the plurality of mannose moieties and to the at least one immunomodulatory drug is backfolded by a rapid dilution step, and wherein the immunomodulatory drug is covalently bound to said HSA via a drug linker selected from pyridinyldithio ethyl carbonate, pyridinyldithio-propionyl-hydrazide, pyridyldithio-ethylamine, SPDP, SPP, SPDB, pyridyldithio-PEGn-NHS, DMAC-SPDP, DMAC-SPP, pyridinyldithio-PEGn- carboxylic acid, PDB-PFP, PDEC-NB, PPC-NB, maleim ide-carboxylic acid, maleimide-amide-PEGn-va-PABC-PNP, maleimide-PEGn-vc-PABC-PNP, mc-vc- PABC-PNP, mc-Val-Cit-PAB-CI, mcc-vc-PAPC-PNP, mcc-PEGn-PABC, mc-va linker, mcc-va linker, mc-va-nhs linker, mcc-va-nhs linker, mc-Gly-Gly-Phe-Gly- PABC, maleim ide-hydrazide, vinylsulfone-carbonate, thiosulfonate linker, hydrazide-maleimide linker, iodoacetamide linker, and methanethiosulfonate linker.

[0427] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0428] A) a human serum albumin (HSA);

[0429] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0430] C) at least one immunomodulatory drug selected from TLR agonist or Cucurbitacin B covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an NHS-PEGn-DBCO interconnecting molecule, and the molar ratio of the interconnecting molecule to HSA is comprised between 3 and 59, wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59, wherein the molar ratio of the immunomodulatory drug to HSA is comprised between 1 and 30, and wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties are selected from the group consisting of ManpNs, ManpsNs, (Manp)3N3, and (Manp3)3N3, preferably ManpsNs, and wherein the HSA bound to the plurality of mannose moieties and to the at least one immunomodulatory drug is backfolded by a rapid dilution step, and wherein the immunomodulatory drug is covalently bound to said HSA via a drug linker selected from pyridinyldithio ethyl carbonate, pyridinyldithio- propionyl-hydrazide, pyridyldithio-ethylamine, SPDP, SPP, SPDB, pyridyldithio- PEGn-NHS, DMAC-SPDP, DMAC-SPP, pyridinyldithio-PEGn-carboxylic acid, PDB-PFP, PDEC-NB, PPC-NB, maleim ide-carboxylic acid, maleimide-amide- PEGn-va-PABC-PNP, maleimide-PEGn-vc-PABC-PNP, mc-vc-PABC-PNP, mc- Val-Cit-PAB-CI, mcc-vc-PAPC-PNP, mcc-PEGn-PABC, mc-va linker, mcc-va linker, mc-va-nhs linker, mcc-va-nhs linker, mc-Gly-Gly-Phe-Gly-PABC, maleim ide-hydrazide, vinylsulfone-carbonate, thiosulfonate linker, hydrazide- maleimide linker, iodoacetamide linker, and methanethiosulfonate linker.

[0431] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0432] A) a human serum albumin (HSA);

[0433] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0434] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an NHS-PEGn-DBCO interconnecting molecule, and the molar ratio of the interconnecting molecule to HSA is comprised between 3 and 59, wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59, wherein the molar ratio of the immunomodulatory drug to HSA is comprised between 1 and 30, and wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties are selected from the group consisting of ManpNs, ManpsNs, (Manp)3N3, and (Manp3)3N3, preferably ManpsNs, and wherein the HSA bound to the plurality of mannose moieties and to the at least one immunomodulatory drug is backfolded by a rapid dilution step, and wherein the immunomodulatory drug is covalently bound to said HSA via a drug linker selected from pyridinyldithio ethyl carbonate, pyridinyldithio- propionyl-hydrazide, pyridyldithio-ethylamine, SPDP, SPP, SPDB, pyridyldithio- PEGn-NHS, DMAC-SPDP, DMAC-SPP, pyridinyldithio-PEGn-carboxylic acid, PDB-PFP, PDEC-NB, PPC-NB, maleim ide-carboxylic acid, maleimide-amide- PEGn-va-PABC-PNP, maleimide-PEGn-vc-PABC-PNP, mc-vc-PABC-PNP, mc- Val-Cit-PAB-CI, mcc-vc-PAPC-PNP, mcc-PEGn-PABC, mc-va linker, mcc-va linker, mc-va-nhs linker, mcc-va-nhs linker, mc-Gly-Gly-Phe-Gly-PABC, maleim ide-hydrazide, vinylsulfone-carbonate, thiosulfonate linker, hydrazide- maleimide linker, iodoacetamide linker, and methanethiosulfonate linker.

[0435] In another embodiment, the HSA nanocamer system comprises at least one immunomodulatory drug covalently bound to said HSA via a drug linker comprising a thiol-reactive functional group, wherein the linker is covalently bound to a ketone or aldehyde group of the immunomodulatory drug and the linker is selected from methanethiosulfonate, thiosulfonate, and maleimide-hydrazide (e.g. BMPH (N-|3- maleimidopropionic acid hydrazide)). Thus, the present invention is also directed to an HSA-nanocamer system for drug delivery, comprises:

[0436] A) a human serum albumin (HSA);

[0437] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0438] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, and wherein the immunomodulatory drug is covalently bound to said HSA via a drug linker comprising a thiol-reactive functional group, wherein the linker is covalently bound to a ketone or aldehyde group of the immunomodulatory drug and the linker is selected from methanethiosulfonate, thiosulfonate, and maleimide-hydrazide (e.g. BMPH (N-[3-maleimidopropionic acid hydrazide)).

[0439] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0440] A) a human serum albumin (HSA);

[0441] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0442] C) at least one immunomodulatory drug selected from TLR7 / 8 agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, and wherein the immunomodulatory drug is covalently bound to said HSA via a drug linker comprising a thiol-reactive functional group, wherein the linker is covalently bound to a ketone or aldehyde group of the immunomodulatory drug and the linker is selected from methanethiosulfonate, thiosulfonate, and maleimide-hydrazide (e.g. BMPH (N-[3-maleimidopropionic acid hydrazide)).

[0443] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0444] A) a human serum albumin (HSA);

[0445] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0446] C) at least one immunomodulatory drug selected from TLR7 / 8 agonist or Cucurbitacin B covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, and wherein the immunomodulatory drug is covalently bound to said HSA via a drug linker comprising a thiol-reactive functional group, wherein the linker is covalently bound to a ketone or aldehyde group of the immunomodulatory drug and the linker is selected from methanethiosulfonate, thiosulfonate, and maleimide-hydrazide (e.g. BMPH (N-[3-maleimidopropionic acid hydrazide)).

[0447] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0448] A) a human serum albumin (HSA);

[0449] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA; C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an interconnecting molecule comprising polyethylene glycol with a number of ethylene glycol repeating units between 2 and 10, and wherein the immunomodulatory drug is covalently bound to said HSA via a drug linker comprising a thiol-reactive functional group, wherein the linker is covalently bound to a ketone or aldehyde group of the immunomodulatory drug and the linker is selected from methanethiosulfonate, thiosulfonate, and maleimide-hydrazide (e.g. BMPH (N-[3-maleimidopropionic acid hydrazide)).

[0450] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0451] A) a human serum albumin (HSA);

[0452] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0453] C) at least one immunomodulatory drug selected from TLR7 / 8 agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an NHS-PEGn-DBCO interconnecting molecule, and wherein the immunomodulatory drug is covalently bound to said HSA via a drug linker comprising a thiol-reactive functional group, wherein the linker is covalently bound to a ketone or aldehyde group of the immunomodulatory drug and the linker is selected from methanethiosulfonate, thiosulfonate, and maleimide-hydrazide (e.g. BMPH (N-[3-maleimidopropionic acid hydrazide)).

[0454] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0455] A) a human serum albumin (HSA);

[0456] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0457] C) at least one immunomodulatory drug selected from TLR7 / 8 agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an interconnecting molecule selected from NHS- DBCO, NHS-PEGn-DBCO, BCN-Endo-NHS, BCN-Endo-PEGn-NHS, NHS-DIBO, NHS-PEGn-DIBO, NHS-DIFO, NHS-PEGn-DIFO, NHS-BCN, NHS-PEGn-BCN, NHS-TCO, NHS-PEGn-TCO, NHS-alkyne, NHS-PEGn-alkyne, NHS-azide, NHS- PEGn-Azide, STP-DBCO, STP-PEGn-DBCO, BCN-Endo-STP, BCN-Endo-PEGn- STP, STP-DIBO, STP-PEGn-DIBO, STP-DIFO, STP-PEGn-DIFO, STP-BCN, STP-PEGn-BCN, STP-TCO, STP-PEGn-TCO, STP-alkyne, STP-PEGn-alkyne, STP-azide, STP-PEGn-Azide, TFP-DBCO, TFP-PEGn-DBCO, BCN-Endo-TFP, BCN-Endo-PEGn-TFP, TFP-DIBO, TFP-PEGn-DIBO, TFP-DIFO, TFP-PEGn- DIFO, TFP-BCN, TFP-PEGn-BCN, TFP-TCO, TFP-PEGn-TCO, TFP-alkyne, TFP- PEGn-alkyne, TFP-azide, TFP-PEGn-Azide, PTP-DBCO, PTP-PEGn-DBCO, BCN-Endo-PTP, BCN-Endo-PEGn-PTP, PTP-DIBO, PTP-PEGn-DIBO, PTP- DIFO, PTP-PEGn-DIFO, PTP-BCN, PTP-PEGn-BCN, PTP-TCO, PTP-PEGn- TCO, PTP-alkyne, PTP-PEGn-alkyne, PTP-azide, PTP-PEGn-Azide, NPC-DBCO, NPC-PEGn-DBCO, BCN-Endo-NPC, BCN-Endo-PEGn-NPC, NPC-DIBO, NPC- PEGn-DIBO, NPC-DIFO, NPC-PEGn-DIFO, NPC-BCN, NPC-PEGn-BCN, NPC- TCO, NPC-PEGn-TCO, NPC-alkyne, NPC-PEGn-alkyne, NPC-azide, NPC-PEGn- Azide, NCS-azide, NCS-PEGn-azide, NCS-alkyne, NCS-PEGn-alkyne, NCS- DBCO, NCS-PEGn-DBCO, BCN-Endo-NCS, BCN-Endo-PEGn-NCS, NCS-DIBO, NCS-PEGn-DIBO, NCS-DIFO, NCS-PEGn-DIFO, NCS-BCN, NCS-PEGn-BCN, DBCO-COOH, DBCO-PEGn-COOH, BCN-Endo-COOH, BCN-Endo-PEGn- COOH, BCN-COOH, BCN-PEGn-COOH, DIBO-COOH, DIBO-PEGn-COOH, DIFO-COOH, DIFO-PEGn-COOH, Alkyne-COOH, and Alkyne-PEGn-COOH, wherein n represents the number of ethylene glycol repeating units between 2 and 10, and wherein the immunomodulatory drug is covalently bound to said HSA via a drug linker comprising a thiol-reactive functional group, wherein the linker is covalently bound to a ketone or aldehyde group of the immunomodulatory drug and the linker is selected from methanethiosulfonate, thiosulfonate, and maleimide-hydrazide (e.g. BMPH (N-[3-maleimidopropionic acid hydrazide)).

[0458] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0459] A) a human serum albumin (HSA);

[0460] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0461] C) at least one immunomodulatory drug selected from TLR7 / 8 agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, and wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an NHS-PEGn-DBCO interconnecting molecule, and the molar ratio of the interconnecting molecule to HSA is comprised between 3 and 59, and / or wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59, and wherein the immunomodulatory drug is covalently bound to said HSA via a drug linker comprising a thiol-reactive functional group, wherein the linker is covalently bound to a ketone or aldehyde group of the immunomodulatory drug and the linker is selected from methanethiosulfonate, thiosulfonate, and maleimide-hydrazide (e.g. BMPH (N-[3-maleimidopropionic acid hydrazide)).

[0462] In a preferred embodiment, the HSA-nanocamer system for drug delivery, comprises:

[0463] A) a human serum albumin (HSA);

[0464] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0465] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, and wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an NHS-PEGn-DBCO interconnecting molecule, and the molar ratio of the interconnecting molecule to HSA is comprised between 3 and 59, and wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59, and wherein the immunomodulatory drug is covalently bound to said HSA via a drug linker comprising a thiol-reactive functional group, wherein the linker is covalently bound to a ketone or aldehyde group of the immunomodulatory drug and the linker is selected from methanethiosulfonate, thiosulfonate, and maleimide-hydrazide (e.g. BMPH (N-[3-maleimidopropionic acid hydrazide)).

[0466] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0467] A) a human serum albumin (HSA);

[0468] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0469] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an NHS-PEGn-DBCO interconnecting molecule, and the molar ratio of the interconnecting molecule to HSA is comprised between 3 and 59, wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59, wherein the molar ratio of the immunomodulatory drug to HSA is comprised between 1 and 30, and wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties are selected from the group consisting of ManpNs, ManpsNs, (Manp)3N3, and (Manp3)3N3, preferably ManpsNs, and wherein the immunomodulatory drug is covalently bound to said HSA via a drug linker comprising a thiol-reactive functional group, wherein the linker is covalently bound to a ketone or aldehyde group of the immunomodulatory drug and the linker is selected from methanethiosulfonate, thiosulfonate, and maleimide-hydrazide (e.g. BMPH (N-[3-maleimidopropionic acid hydrazide)).

[0470] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0471] A) a human serum albumin (HSA);

[0472] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0473] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an interconnecting molecule comprising polyethylene glycol with a number of ethylene glycol repeating units between 2 and 10, and the molar ratio of the interconnecting molecule to HSA is comprised between 3 and 59, wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59, wherein the molar ratio of the immunomodulatory drug to HSA is comprised between 1 and 30, and wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties are selected from the group consisting of ManpNs, ManpsNs, (Manp)3N3, and (Manp3)3N3, preferably ManpsNs, and wherein the HSA bound to the plurality of mannose moieties and to the at least one immunomodulatory drug is backfolded by a rapid dilution step, and wherein the immunomodulatory drug is covalently bound to said via a drug linker comprising a thiol-reactive functional group, wherein the linker is covalently bound to a ketone or aldehyde group of the immunomodulatory drug and the linker is selected from methanethiosulfonate, thiosulfonate, and maleimide-hydrazide (e.g. BMPH (N-[3-maleimidopropionic acid hydrazide)).

[0474] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0475] A) a human serum albumin (HSA);

[0476] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0477] C) at least one immunomodulatory drug selected from TLR agonist or Cucurbitacin B covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an NHS-PEGn-DBCO interconnecting molecule, and the molar ratio of the interconnecting molecule to HSA is comprised between 3 and 59, wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59, wherein the molar ratio of the immunomodulatory drug to HSA is comprised between 1 and 30, and wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties are selected from the group consisting of ManpNs, ManpsNs, (Manp)3N3, and (Manp3)3N3, preferably ManpsNs, and wherein the HSA bound to the plurality of mannose moieties and to the at least one immunomodulatory drug is backfolded by a rapid dilution step, and wherein the immunomodulatory drug is covalently bound to said HSA via a drug linker comprising a thiol-reactive functional group, wherein the linker is covalently bound to a ketone or aldehyde group of the immunomodulatory drug and the linker is selected from methanethiosulfonate, thiosulfonate, and maleimide-hydrazide (e.g. BMPH (N-[3-maleimidopropionic acid hydrazide)).

[0478] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0479] A) a human serum albumin (HSA);

[0480] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0481] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an NHS-PEGn-DBCO interconnecting molecule, and the molar ratio of the interconnecting molecule to HSA is comprised between 3 and 59, wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59, wherein the molar ratio of the immunomodulatory drug to HSA is comprised between 1 and 30, and wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties are selected from the group consisting of ManpNs, ManpsNs, (Manp)3N3, and (Manp3)3N3, preferably ManpsNs, and wherein the HSA bound to the plurality of mannose moieties and to the at least one immunomodulatory drug is backfolded by a rapid dilution step, and wherein the immunomodulatory drug is covalently bound to said HSA via a drug linker comprising a thiol-reactive functional group, wherein the linker is covalently bound to a ketone or aldehyde group of the immunomodulatory drug and the linker is selected from methanethiosulfonate, thiosulfonate, and maleimide-hydrazide (e.g. BMPH (N-[3-maleimidopropionic acid hydrazide)).

[0482] In a preferred embodiment, the HSA nanocarrier system further comprises a fluorescent dye. Thus, HSA-nanocamer system for drug delivery, comprises:

[0483] A) a human serum albumin (HSA);

[0484] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0485] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA

[0486] D) a fluorescent dye covalently bound to said HSA, wherein the fluorescent dye comprises a maleimide as thiol-reactive functional group or an NHS- ester as amine-reactive functional group, and wherein the fluorescent dye emits light in a range of 400 nm to 850 nm; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering.

[0487] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0488] A) a human serum albumin (HSA);

[0489] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0490] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA

[0491] D) a fluorescent dye covalently bound to said HSA, wherein the fluorescent dye comprises a maleimide as thiol-reactive functional group or an NHS- ester as amine-reactive functional group, and wherein the fluorescent dye emits light in a range of 400 nm to 850 nm; the fluorescent dye is a fluorescent dye maleimide selected from the group consisting of sulfo-cyanin-maleimide, Alexa Fluor-maleimide, and cyanin- maleimide; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering.

[0492] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0493] A) a human serum albumin (HSA);

[0494] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0495] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA;

[0496] D) a fluorescent dye covalently bound to said HSA, wherein the fluorescent dye comprises a maleimide as thiol-reactive functional group or an NHS- ester as amine-reactive functional group, and wherein the fluorescent dye emits light in a range of 400 nm to 850 nm the fluorescent dye is a fluorescent dye maleimide selected from the group consisting of sulfo-cyanin-maleimide, Alexa Fluor-maleimide, and cyanin- maleimide; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, and wherein the immunomodulatory drug is covalently bound to said HSA via a drug linker selected from pyridinyldithio ethyl carbonate, pyridinyldithio-propionyl-hydrazide, pyridyldithio-ethylamine, SPDP, SPP, SPDB, pyridyldithio-PEGn-NHS, DMAC- SPDP, DMAC-SPP, pyridinyldithio-PEGn-carboxylic acid, PDB-PFP, PDEC-NB, PPC-NB, maleimide-carboxylic acid, maleimide-amide-PEGn-va-PABC-PNP, maleimide-PEGn-vc-PABC-PNP, mc-vc-PABC-PNP, mc-Val-Cit-PAB-CI, mcc-vc- PAPC-PNP, mcc-PEGn-PABC, mc-va linker, mcc-va linker, mc-va-nhs linker, mcc- va-nhs linker, mc-Gly-Gly-Phe-Gly-PABC, maleimide-hydrazide, vinylsulfone- carbonate, thiosulfonate linker, hydrazide-maleimide linker, iodoacetamide linker, and methanethiosulfonate linker.

[0497] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0498] A) a human serum albumin (HSA);

[0499] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA; C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA;

[0500] D) a fluorescent dye covalently bound to said HSA, wherein the fluorescent dye comprises a maleimide as thiol-reactive functional group or an NHS- ester as amine-reactive functional group, and wherein the fluorescent dye emits light in a range of 400 nm to 850 nm the fluorescent dye is a fluorescent dye maleimide selected from the group consisting of sulfo-cyanin-maleimide, Alexa Fluor-maleimide, and cyanin- maleimide; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, and wherein the immunomodulatory drug is covalently bound to said HSA via a drug linker comprising a thiol-reactive functional group, wherein the linker is covalently bound to a ketone or aldehyde group of the immunomodulatory drug and the linker is selected from methanethiosulfonate, thiosulfonate, and maleimide-hydrazide (e.g. BMPH (N-[3-maleimidopropionic acid hydrazide)).

[0501] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0502] A) a human serum albumin (HSA);

[0503] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0504] C) at least one immunomodulatory drug selected from TLR7 / 8 agonist or STAT3 inhibitor covalently bound to said HSA;

[0505] D) a fluorescent dye covalently bound to said HSA, wherein the fluorescent dye comprises a maleimide as thiol-reactive functional group or an NHS- ester as amine-reactive functional group, and wherein the fluorescent dye emits light in a range of 400 nm to 850 nm; the fluorescent dye is a fluorescent dye maleimide selected from the group consisting of sulfo-cyanin-maleimide, Alexa Fluor-maleimide, and cyanin- maleimide; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering.

[0506] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0507] A) a human serum albumin (HSA);

[0508] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA; C) at least one immunomodulatory drug selected from TLR7 / 8 agonist or Cucurbitacin B covalently bound to said HSA;

[0509] D) a fluorescent dye covalently bound to said HSA, wherein the fluorescent dye comprises a maleimide as thiol-reactive functional group or an NHS- ester as amine-reactive functional group, and wherein the fluorescent dye emits light in a range of 400 nm to 850 nm the fluorescent dye is a fluorescent dye maleimide selected from the group consisting of sulfo-cyanin-maleimide, Alexa Fluor-maleimide, and cyanin- maleimide; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering.

[0510] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0511] A) a human serum albumin (HSA);

[0512] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0513] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA;

[0514] D) a fluorescent dye covalently bound to said HSA, wherein the fluorescent dye comprises a maleimide as thiol-reactive functional group or an NHS- ester as amine-reactive functional group, and wherein the fluorescent dye emits light in a range of 400 nm to 850 nm the fluorescent dye is a fluorescent dye maleimide selected from the group consisting of sulfo-cyanin-maleimide, Alexa Fluor-maleimide, and cyanin- maleimide; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an interconnecting molecule comprising polyethylene glycol with a number of ethylene glycol repeating units between 2 and 10.

[0515] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0516] A) a human serum albumin (HSA);

[0517] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0518] C) at least one immunomodulatory drug selected from TLR7 / 8 agonist or STAT3 inhibitor covalently bound to said HSA; D) a fluorescent dye covalently bound to said HSA, wherein the fluorescent dye comprises a maleimide as thiol-reactive functional group or an NHS- ester as amine-reactive functional group, and wherein the fluorescent dye emits light in a range of 400 nm to 850 nm; the fluorescent dye is a fluorescent dye maleimide selected from the group consisting of sulfo-cyanin-maleimide, Alexa Fluor-maleimide, and cyanin- maleimide; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an NHS-PEGn-DBCO interconnecting molecule.

[0519] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0520] A) a human serum albumin (HSA);

[0521] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0522] C) at least one immunomodulatory drug selected from TLR7 / 8 agonist or STAT3 inhibitor covalently bound to said HSA;

[0523] D) a fluorescent dye covalently bound to said HSA, wherein the fluorescent dye comprises a maleimide as thiol-reactive functional group or an NHS- ester as amine-reactive functional group, and wherein the fluorescent dye emits light in a range of 400 nm to 850 nm; the fluorescent dye is a fluorescent dye maleimide selected from the group consisting of sulfo-cyanin-maleimide, Alexa Fluor-maleimide, and cyanin- maleimide; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an interconnecting molecule selected from NHS- DBCO, NHS-PEGn-DBCO, BCN-Endo-NHS, BCN-Endo-PEGn-NHS, NHS-DIBO, NHS-PEGn-DIBO, NHS-DIFO, NHS-PEGn-DIFO, NHS-BCN, NHS-PEGn-BCN, NHS-TCO, NHS-PEGn-TCO, NHS-alkyne, NHS-PEGn-alkyne, NHS-azide, NHS- PEGn-Azide, STP-DBCO, STP-PEGn-DBCO, BCN-Endo-STP, BCN-Endo-PEGn- STP, STP-DIBO, STP-PEGn-DIBO, STP-DIFO, STP-PEGn-DIFO, STP-BCN, STP-PEGn-BCN, STP-TCO, STP-PEGn-TCO, STP-alkyne, STP-PEGn-alkyne, STP-azide, STP-PEGn-Azide, TFP-DBCO, TFP-PEGn-DBCO, BCN-Endo-TFP, BCN-Endo-PEGn-TFP, TFP-DIBO, TFP-PEGn-DIBO, TFP-DIFO, TFP-PEGn- DIFO, TFP-BCN, TFP-PEGn-BCN, TFP-TCO, TFP-PEGn-TCO, TFP-alkyne, TFP- PEGn-alkyne, TFP-azide, TFP-PEGn-Azide, PTP-DBCO, PTP-PEGn-DBCO, BCN-Endo-PTP, BCN-Endo-PEGn-PTP, PTP-DIBO, PTP-PEGn-DIBO, PTP- DIFO, PTP-PEGn-DIFO, PTP-BCN, PTP-PEGn-BCN, PTP-TCO, PTP-PEGn- TCO, PTP-alkyne, PTP-PEGn-alkyne, PTP-azide, PTP-PEGn-Azide, NPC-DBCO, NPC-PEGn-DBCO, BCN-Endo-NPC, BCN-Endo-PEGn-NPC, NPC-DIBO, NPC- PEGn-DIBO, NPC-DIFO, NPC-PEGn-DIFO, NPC-BCN, NPC-PEGn-BCN, NPC- TCO, NPC-PEGn-TCO, NPC-alkyne, NPC-PEGn-alkyne, NPC-azide, NPC-PEGn- Azide, NCS-azide, NCS-PEGn-azide, NCS-alkyne, NCS-PEGn-alkyne, NCS- DBCO, NCS-PEGn-DBCO, BCN-Endo-NCS, BCN-Endo-PEGn-NCS, NCS-DIBO, NCS-PEGn-DIBO, NCS-DIFO, NCS-PEGn-DIFO, NCS-BCN, NCS-PEGn-BCN, DBCO-COOH, DBCO-PEGn-COOH, BCN-Endo-COOH, BCN-Endo-PEGn- COOH, BCN-COOH, BCN-PEGn-COOH, DIBO-COOH, DIBO-PEGn-COOH, DIFO-COOH, DIFO-PEGn-COOH, Alkyne-COOH, and Alkyne-PEGn-COOH, wherein n represents the number of ethylene glycol repeating units between 2 and 10.

[0524] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0525] A) a human serum albumin (HSA);

[0526] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0527] C) at least one immunomodulatory drug selected from TLR7 / 8 agonist or STAT3 inhibitor covalently bound to said HSA;

[0528] D) a fluorescent dye covalently bound to said HSA, wherein the fluorescent dye comprises a maleimide as thiol-reactive functional group or an NHS- ester as amine-reactive functional group, and wherein the fluorescent dye emits light in a range of 400 nm to 850 nm; the fluorescent dye is a fluorescent dye maleimide selected from the group consisting of sulfo-cyanin-maleimide, Alexa Fluor-maleimide, and cyanin- maleimide; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, and wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an NHS-PEGn-DBCO interconnecting molecule, and the molar ratio of the interconnecting molecule to HSA is comprised between 3 and 59, and / or wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59. In a preferred embodiment, the HSA-nanocarrier system for drug delivery, comprises:

[0529] A) a human serum albumin (HSA);

[0530] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0531] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA;

[0532] D) a fluorescent dye covalently bound to said HSA, wherein the fluorescent dye comprises a maleimide as thiol-reactive functional group or an NHS- ester as amine-reactive functional group, and wherein the fluorescent dye emits light in a range of 400 nm to 850 nm; the fluorescent dye is a fluorescent dye maleimide selected from the group consisting of sulfo-cyanin-maleimide, Alexa Fluor-maleimide, and cyanin- maleimide; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, and wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an NHS-PEGn-DBCO interconnecting molecule, and the molar ratio of the interconnecting molecule to HSA is comprised between 3 and 59, and wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59.

[0533] Preferably, the HSA-nanocarrier system for drug delivery, comprises:

[0534] A) a human serum albumin (HSA);

[0535] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0536] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA;

[0537] D) a fluorescent dye covalently bound to said HSA, wherein the fluorescent dye comprises a maleimide as thiol-reactive functional group or an NHS- ester as amine-reactive functional group, and wherein the fluorescent dye emits light in a range of 400 nm to 850 nm; the fluorescent dye is a fluorescent dye maleimide selected from the group consisting of sulfo-cyanin-maleimide, Alexa Fluor-maleimide, and cyanin- maleimide; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an NHS-PEGn-DBCO interconnecting molecule, and the molar ratio of the interconnecting molecule to HSA is comprised between 3 and 59, wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59, wherein the molar ratio of the immunomodulatory drug to HSA is comprised between 1 and 30, and wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties are selected from the group consisting of ManpNs, ManpsNs, (Manp)3N3, and (Manp3)3N3, preferably ManpsNs.

[0538] Preferably, the HSA-nanocarrier system for drug delivery, comprises:

[0539] A) a human serum albumin (HSA);

[0540] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0541] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA;

[0542] D) a fluorescent dye covalently bound to said HSA, wherein the fluorescent dye comprises a maleimide as thiol-reactive functional group or an NHS- ester as amine-reactive functional group, and wherein the fluorescent dye emits light in a range of 400 nm to 850 nm; the fluorescent dye is a fluorescent dye maleimide selected from the group consisting of sulfo-cyanin-maleimide, Alexa Fluor-maleimide, and cyanin- maleimide; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an interconnecting molecule comprising polyethylene glycol with a number of ethylene glycol repeating units between 2 and 10, and the molar ratio of the interconnecting molecule to HSA is comprised between 3 and 59, wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59, wherein the molar ratio of the immunomodulatory drug to HSA is comprised between 1 and 30, and wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties are selected from the group consisting of ManpNs, ManpsNs, (Manp)3N3, and (Manp3)3N3, preferably ManpsNs, and wherein the HSA bound to the plurality of mannose moieties and to the at least one immunomodulatory drug is backfolded by a rapid dilution step.

[0543] Preferably, the HSA-nanocarrier system for drug delivery, comprises: A) a human serum albumin (HSA);

[0544] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0545] C) at least one immunomodulatory drug selected from TLR agonist or Cucurbitacin B covalently bound to said HSA;

[0546] D) a fluorescent dye covalently bound to said HSA, wherein the fluorescent dye comprises a maleimide as thiol-reactive functional group or an NHS- ester as amine-reactive functional group, and wherein the fluorescent dye emits light in a range of 400 nm to 850 nm; the fluorescent dye is a fluorescent dye maleimide selected from the group consisting of sulfo-cyanin-maleimide, Alexa Fluor-maleimide, and cyanin- maleimide; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an NHS-PEGn-DBCO interconnecting molecule, and the molar ratio of the interconnecting molecule to HSA is comprised between 3 and 59, wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59, wherein the molar ratio of the immunomodulatory drug to HSA is comprised between 1 and 30, and wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties are selected from the group consisting of ManpNs, ManpsNs, (Manp)3N3, and (Manp3)3N3, preferably ManpsNs, and wherein the HSA bound to the plurality of mannose moieties and to the at least one immunomodulatory drug is backfolded by a rapid dilution step, and wherein the immunomodulatory drug is covalently bound to said HSA via a drug linker selected from pyridinyldithio ethyl carbonate, pyridinyldithio- propionyl-hydrazide, pyridyldithio-ethylamine, SPDP, SPP, SPDB, pyridyldithio- PEGn-NHS, DMAC-SPDP, DMAC-SPP, pyridinyldithio-PEGn-carboxylic acid, PDB-PFP, PDEC-NB, PPC-NB, maleim ide-carboxylic acid, maleimide-amide- PEGn-va-PABC-PNP, maleimide-PEGn-vc-PABC-PNP, mc-vc-PABC-PNP, mc- Val-Cit-PAB-CI, mcc-vc-PAPC-PNP, mcc-PEGn-PABC, mc-va linker, mcc-va linker, mc-va-nhs linker, mcc-va-nhs linker, mc-Gly-Gly-Phe-Gly-PABC, maleim ide-hydrazide, vinylsulfone-carbonate, thiosulfonate linker, hydrazide- maleimide linker, iodoacetamide linker, and methanethiosulfonate linker.

[0547] Preferably, the drug linker comprises a thiol-reactive functional group selected from pyridinyldithio-ethoxy-carbonyl-group, maleimide, mc-vc-pabc linker (maleimidocaproyl (me) - valine-citrulline (vc) -para-amino benzyloxycarbonyl (PABC)), thiosulfonate linker, hydrazide-maleimide linker, iodoacetamide linker, and methanethiosulfonate linker.

[0548] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0549] A) a human serum albumin (HSA);

[0550] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0551] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA;

[0552] D) a fluorescent dye covalently bound to said HSA, wherein the fluorescent dye comprises a maleimide as thiol-reactive functional group or an NHS- ester as amine-reactive functional group, and wherein the fluorescent dye emits light in a range of 400 nm to 850 nm; the fluorescent dye is a fluorescent dye maleimide selected from the group consisting of sulfo-cyanin-maleimide, Alexa Fluor-maleimide, and cyanin- maleimide; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an NHS-PEGn-DBCO interconnecting molecule, and the molar ratio of the interconnecting molecule to HSA is comprised between 3 and 59, wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59, wherein the molar ratio of the immunomodulatory drug to HSA is comprised between 1 and 30, and wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties are selected from the group consisting of ManpNs, ManpsNs, (Manp)3N3, and (Manp3)3N3, preferably ManpsNs, and wherein the HSA bound to the plurality of mannose moieties and to the at least one immunomodulatory drug is backfolded by a rapid dilution step, and wherein the immunomodulatory drug is covalently bound to said HSA via a drug linker comprising a thiol-reactive functional group, wherein the linker is covalently bound to a ketone or aldehyde group of the immunomodulatory drug and the linker is selected from methanethiosulfonate, thiosulfonate, and maleimide-hydrazide (e.g. BMPH (N-[3-maleimidopropionic acid hydrazide)).

[0553] In a preferred embodiment the HSA-nanocamer system for drug delivery, comprises:

[0554] A) a human serum albumin (HSA); B) a plurality of dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0555] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering.

[0556] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0557] A) a human serum albumin (HSA);

[0558] B) a plurality of dimannose moieties or trimannose moieties covalently bound to said HSA;

[0559] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering.

[0560] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0561] A) a human serum albumin (HSA);

[0562] B) a plurality of dimannose moieties or trimannose moieties covalently bound to said HSA;

[0563] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA the fluorescent dye is a fluorescent dye maleimide selected from the group consisting of sulfo-cyanin-maleimide, Alexa Fluor-maleimide, and cyanin- maleimide; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering.

[0564] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0565] A) a human serum albumin (HSA);

[0566] B) a plurality of dimannose moieties or trimannose moieties covalently bound to said HSA;

[0567] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, and wherein the immunomodulatory drug is covalently bound to said HSA via a drug linker selected from pyridinyldithio ethyl carbonate, pyridinyldithio-propionyl-hydrazide, pyridyldithio-ethylamine, SPDP, SPP, SPDB, pyridyldithio-PEGn-NHS, DMAC- SPDP, DMAC-SPP, pyridinyldithio-PEGn-carboxylic acid, PDB-PFP, PDEC-NB, PPC-NB, maleimide-carboxylic acid, maleimide-amide-PEGn-va-PABC-PNP, maleimide-PEGn-vc-PABC-PNP, mc-vc-PABC-PNP, mc-Val-Cit-PAB-CI, mcc-vc- PAPC-PNP, mcc-PEGn-PABC, mc-va linker, mcc-va linker, mc-va-nhs linker, mcc- va-nhs linker, mc-Gly-Gly-Phe-Gly-PABC, maleimide-hydrazide, vinylsulfone- carbonate, thiosulfonate linker, hydrazide-maleimide linker, iodoacetamide linker, and methanethiosulfonate linker

[0568] Preferabyl, the drug linker comprises a thiol-reactive functional group selected from selected from pyridinyldithio-ethoxy-carbonyl-group, maleimide, mc-vc-pabc linker (maleimidocaproyl (me) - valine-citrulline (vc) -para-amino benzyloxycarbonyl (PABC)), thiosulfonate linker, hydrazide-maleimide linker, iodoacetamide linker, and methanethiosulfonate linker.

[0569] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0570] A) a human serum albumin (HSA);

[0571] B) a plurality of dimannose moieties or trimannose moieties covalently bound to said HSA;

[0572] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, and wherein the immunomodulatory drug is covalently bound to said HSA via a drug linker comprising a thiol-reactive functional group, wherein the linker is covalently bound to a ketone or aldehyde group of the immunomodulatory drug and the linker is selected from methanethiosulfonate, thiosulfonate, and maleimide-hydrazide (e.g. BMPH (N-[3-maleimidopropionic acid hydrazide)).

[0573] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0574] A) a human serum albumin (HSA);

[0575] B) a plurality of dimannose moieties or trimannose moieties covalently bound to said HSA;

[0576] C) at least one immunomodulatory drug selected from TLR7 / 8 agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering. Preferably, the HSA-nanocarrier system for drug delivery, comprises:

[0577] A) a human serum albumin (HSA);

[0578] B) a plurality of dimannose moieties or trimannose moieties covalently bound to said HSA;

[0579] C) at least one immunomodulatory drug selected from TLR7 / 8 agonist or Cucurbitacin B covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering.

[0580] Preferably, the HSA-nanocarrier system for drug delivery, comprises:

[0581] A) a human serum albumin (HSA);

[0582] B) a plurality of dimannose moieties or trimannose moieties covalently bound to said HSA;

[0583] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of dimannose moieties or trimannose moieties is covalently bound to the HSA via an interconnecting molecule comprising polyethylene glycol with a number of ethylene glycol repeating units between 2 and 10.

[0584] Preferably, the HSA-nanocarrier system for drug delivery, comprises:

[0585] A) a human serum albumin (HSA);

[0586] B) a plurality of dimannose moieties or trimannose moieties covalently bound to said HSA;

[0587] C) at least one immunomodulatory drug selected from TLR7 / 8 agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of dimannose moieties or trimannose moieties is covalently bound to the HSA via an NHS-PEGn-DBCO interconnecting molecule.

[0588] Preferably, the HSA-nanocarrier system for drug delivery, comprises:

[0589] A) a human serum albumin (HSA);

[0590] B) a plurality of dimannose moieties or trimannose moieties covalently bound to said HSA;

[0591] C) at least one immunomodulatory drug selected from TLR7 / 8 agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of dimannose moieties or trimannose moieties is covalently bound to the HSA via an interconnecting molecule selected from NHS-DBCO, NHS-PEGn- DBCO, BCN-Endo-NHS, BCN-Endo-PEGn-NHS, NHS-DIBO, NHS-PEGn-DIBO, NHS-DIFO, NHS-PEGn-DIFO, NHS-BCN, NHS-PEGn-BCN, NHS-TCO, NHS- PEGn-TCO, NHS-alkyne, NHS-PEGn-alkyne, NHS-azide, NHS-PEGn-Azide, STP-DBCO, STP-PEGn-DBCO, BCN-Endo-STP, BCN-Endo-PEGn-STP, STP- DIBO, STP-PEGn-DIBO, STP-DIFO, STP-PEGn-DIFO, STP-BCN, STP-PEGn- BCN, STP-TCO, STP-PEGn-TCO, STP-alkyne, STP-PEGn-alkyne, STP-azide, STP-PEGn-Azide, TFP-DBCO, TFP-PEGn-DBCO, BCN-Endo-TFP, BCN-Endo- PEGn-TFP, TFP-DIBO, TFP-PEGn-DIBO, TFP-DIFO, TFP-PEGn-DIFO, TFP- BCN, TFP-PEGn-BCN, TFP-TCO, TFP-PEGn-TCO, TFP-alkyne, TFP-PEGn- alkyne, TFP-azide, TFP-PEGn-Azide, PTP-DBCO, PTP-PEGn-DBCO, BCN-Endo- PTP, BCN-Endo-PEGn-PTP, PTP-DIBO, PTP-PEGn-DIBO, PTP-DIFO, PTP- PEGn-DIFO, PTP-BCN, PTP-PEGn-BCN, PTP-TCO, PTP-PEGn-TCO, PTP- alkyne, PTP-PEGn-alkyne, PTP-azide, PTP-PEGn-Azide, NPC-DBCO, NPC- PEGn-DBCO, BCN-Endo-NPC, BCN-Endo-PEGn-NPC, NPC-DIBO, NPC-PEGn- DIBO, NPC-DIFO, NPC-PEGn-DIFO, NPC-BCN, NPC-PEGn-BCN, NPC-TCO, NPC-PEGn-TCO, NPC-alkyne, NPC-PEGn-alkyne, NPC-azide, NPC-PEGn-Azide, NCS-azide, NCS-PEGn-azide, NCS-alkyne, NCS-PEGn-alkyne, NCS-DBCO, NCS-PEGn-DBCO, BCN-Endo-NCS, BCN-Endo-PEGn-NCS, NCS-DIBO, NCS- PEGn-DIBO, NCS-DIFO, NCS-PEGn-DIFO, NCS-BCN, NCS-PEGn-BCN, DBCO- COOH, DBCO-PEGn-COOH, BCN-Endo-COOH, BCN-Endo-PEGn-COOH, BCN- COOH, BCN-PEGn-COOH, DIBO-COOH, DIBO-PEGn-COOH, DIFO-COOH, DIFO-PEGn-COOH, Alkyne-COOH, and Alkyne-PEGn-COOH, wherein n represents the number of ethylene glycol repeating units between 2 and 10.

[0592] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0593] A) a human serum albumin (HSA);

[0594] B) a plurality of dimannose moieties or trimannose moieties covalently bound to said HSA;

[0595] C) at least one immunomodulatory drug selected from TLR7 / 8 agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, and wherein the plurality of dimannose moieties or trimannose moieties is covalently bound to the HSA via an NHS-PEGn-DBCO interconnecting molecule, and the molar ratio of the interconnecting molecule to HSA is comprised between 3 and 59, and / or wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59.

[0596] In a preferred embodiment, the HSA-nanocamer system for drug delivery, comprises:

[0597] A) a human serum albumin (HSA);

[0598] B) a plurality of dimannose moieties or trimannose moieties covalently bound to said HSA;

[0599] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, and wherein the plurality of dimannose moieties or trimannose moieties is covalently bound to the HSA via an NHS-PEGn-DBCO interconnecting molecule, and the molar ratio of the interconnecting molecule to HSA is comprised between 3 and 59, and wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59.

[0600] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0601] A) a human serum albumin (HSA);

[0602] B) a plurality of dimannose moieties or trimannose moieties covalently bound to said HSA;

[0603] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of dimannose moieties or trimannose moieties is covalently bound to the HSA via an NHS-PEGn-DBCO interconnecting molecule, and the molar ratio of the interconnecting molecule to HSA is comprised between 3 and 59, wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59, wherein the molar ratio of the immunomodulatory drug to HSA is comprised between 1 and 30, and wherein the plurality of dimannose moieties or trimannose moieties are selected from the group consisting of ManpsNs, and (Manp3)3N3, preferably ManpsNs.

[0604] Preferably, the HSA-nanocamer system for drug delivery, comprises: A) a human serum albumin (HSA); B) a plurality of dimannose moieties or trimannose moieties covalently bound to said HSA;

[0605] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of dimannose moieties or trimannose moieties is covalently bound to the HSA via an interconnecting molecule comprising polyethylene glycol with a number of ethylene glycol repeating units between 2 and 10, and the molar ratio of the interconnecting molecule to HSA is comprised between 3 and 59, wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59, wherein the molar ratio of the immunomodulatory drug to HSA is comprised between 1 and 30, and wherein the plurality of dimannose moieties or trimannose moieties are selected from the group consisting of ManpsNs, and (Manp3)3N3, preferably ManpsNs, and wherein the HSA bound to the plurality of mannose moieties and to the at least one immunomodulatory drug is backfolded by a rapid dilution step.

[0606] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0607] A) a human serum albumin (HSA);

[0608] B) a plurality of dimannose moieties or trimannose moieties covalently bound to said HSA;

[0609] C) at least one immunomodulatory drug selected from TLR agonist or Cucurbitacin B covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of dimannose moieties or trimannose moieties is covalently bound to the HSA via an NHS-PEGn-DBCO interconnecting molecule, and the molar ratio of the interconnecting molecule to HSA is comprised between 3 and 59, wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59, wherein the molar ratio of the immunomodulatory drug to HSA is comprised between 1 and 30, and wherein the plurality of dimannose moieties or trimannose moieties is selected from the group consisting of ManpsNs, and (Manp3)3N3, preferably ManpsNs, and wherein the HSA bound to the plurality of mannose moieties and to the at least one immunomodulatory drug is backfolded by a rapid dilution step, and wherein the immunomodulatory drug is covalently bound to said HSA via a drug linker selected from pyridinyldithio ethyl carbonate, pyridinyldithio-propionyl-hydrazide, pyridyldithio-ethylamine, SPDP, SPP, SPDB, pyridyldithio-PEGn-NHS, DMAC-SPDP, DMAC-SPP, pyridinyldithio-PEGn- carboxylic acid, PDB-PFP, PDEC-NB, PPC-NB, maleim ide-carboxylic acid, maleimide-amide-PEGn-va-PABC-PNP, maleimide-PEGn-vc-PABC-PNP, mc-vc- PABC-PNP, mc-Val-Cit-PAB-CI, mcc-vc-PAPC-PNP, mcc-PEGn-PABC, mc-va linker, mcc-va linker, mc-va-nhs linker, mcc-va-nhs linker, mc-Gly-Gly-Phe-Gly- PABC, maleim ide-hydrazide, vinylsulfone-carbonate, thiosulfonate linker, hydrazide-maleimide linker, iodoacetamide linker, and methanethiosulfonate linker

[0610] Preferably, the drug linker comprises a thiol-reactive functional group selected from pyridinyldithio-ethoxy-carbonyl-group, maleim ide, mc-vc-pabc linker (maleimidocaproyl (me) - valine-citrulline (vc) -para-amino benzyloxycarbonyl (PABC)), thiosulfonate linker, hydrazide-maleimide linker, iodoacetamide linker, and methanethiosulfonate linker.

[0611] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0612] A) a human serum albumin (HSA);

[0613] B) a plurality dimannose moieties or trimannose moieties covalently bound to said HSA;

[0614] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of dimannose moieties or trimannose moieties is covalently bound to the HSA via an NHS-PEGn-DBCO interconnecting molecule, and the molar ratio of the interconnecting molecule to HSA is comprised between 3 and 59, wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59, wherein the molar ratio of the immunomodulatory drug to HSA is comprised between 1 and 30, and wherein the plurality of dimannose moieties or trimannose moieties are selected from the group consisting of ManpsNs, and (Manp3)3N3, preferably ManpsNs, and wherein the HSA bound to the plurality of mannose moieties and to the at least one immunomodulatory drug is backfolded by a rapid dilution step, and wherein the immunomodulatory drug is covalently bound to said HSA via a drug linker comprising a thiol-reactive functional group, wherein the linker is covalently bound to a ketone or aldehyde group of the immunomodulatory drug and the linker is selected from methanethiosulfonate, thiosulfonate, and maleimide-hydrazide (e.g. BMPH (N-[3-maleimidopropionic acid hydrazide)). The inventive HSA nanocarrier system is particularly effective in targeting liver cells expressing a mannose surface receptor. Therefore, the present invention is also directed to an HSA-nanocarrier system for drug delivery targeted to liver cells expressing a mannose surface receptor, wherein said nanocamer system comprises:

[0615] A) a human serum albumin (HSA);

[0616] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0617] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering.

[0618] In a preferred embodiment, the present invention is directed to an HSA- nanocarrier system for drug delivery targeted to liver cells, wherein said nanocarrier system comprises:

[0619] A) a human serum albumin (HSA);

[0620] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0621] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, and wherein the target liver cells express a mannose surface receptor selected from the group consisting of CD206, CD209, and homologues thereof.

[0622] In a further preferred embodiment, the present invention is directed to an HSA- nanocarrier system for drug delivery targeted to liver cells, wherein said nanocarrier system comprises:

[0623] A) a human serum albumin (HSA);

[0624] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0625] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, and wherein the target liver cells are selected from the group consisting of dendritic cells, macrophages, B cells, T cells, liver non-parenchymal cells, splenic cells, neutrophils, and cultured cells expressing an exogenous surface mannose receptor.

[0626] A particularly preferred embodiment is directed to an HSA nanocarrier system as described herein, wherein said HSA nanocarrier system comprises: trimannose bound via an NHS-PEGn-DBCO interconnecting molecule to HSA at a molar trimannose: HSA range comprised between 1 and 59;

[0627] Cucurbitacin B or a TLR7 / 8 agonist as an immunomodulatory drug at a molar drug: HSA range preferably comprised between 5 and 27, wherein the immunomodulatory drug is covalently bound to said HSA by a traceless, self- immolative pyridinyldithio-ethoxy-carbonyl drug linker; optionally a sulfo-Cyanin5-maleimide dye or a sulfo-Cyanin7.5-maleimide dye conjugated to said HSA and wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm.

[0628] Another aspect of the present invention is directed to a pharmaceutical composition comprising the HSA nanocarrier system as described herein together with a pharmaceutical acceptable excipient.

[0629] Another aspect of the present invention is directed to a method to manufacture a HSA nanocarrier system as described herein, wherein the method comprises the following steps: i.) providing monomolecular native HSA, wherein the monomolecular native HSA is optionally labeled with a fluorescent dye; ii.) attaching an interconnecting molecule to the HSA; iii.) covalently binding of a plurality of monomannose or dimannose or trimannose moieties to the interconnecting molecule to obtain mannosylated HSA; iv.) denaturing of the mannosylated HSA obtained at step iii.; v.-a) covalently binding of at least one immunomodulatory drug to said denatured mannosylated HSA, wherein the one or more immunomodulatory drugs are attached to a drug linker comprising a thiol-reactive functional group; v.-b) capping of unreacted thiols, preferably with N-ethylmaleimide; v.-c) washing the denatured nanocarrier system obtained in step v.-b; vi.) backfolding of the denatured nanocarrier system via rapid dilution procedure; vii.) obtaining a monomolecular HSA nanocarrier system, wherein the at least one immunomodulatory drug is not doxorubicin. In preferred embodiments of the method to manufacture a HSA nanocamer system as described herein, the monomolecular HSA nanocamer system has a molar ratio of the plurality of mannose moieties to HSA comprised between 1 and 59, and / or a molar ratio of the interconnecting molecule to HSA comprised between 3 and 59.

[0630] In preferred embodiments of the method to manufacture a HSA nanocamer system as described herein, the plurality of monomannose moieties, dimannose moieties, or trimannose moieties are selected from the group consisting of ManpNs, ManpsNs, (Manp)3N3, and (Manps^Ns, preferably ManpsNs.

[0631] In preferred embodiments of the method to manufacture a HSA nanocamer system as described herein, the at least one immunomodulatory drug is selected from a TLR agonist, and a STAT3 inhibitor. More preferably, the at least one immunomodulatory drug is selected from a TLR7 / 8 agonist, and a STAT3 inhibitor. More preferably, the at least one immunomodulatory drug is selected from a TLR7 / 8 agonist, and Cucurbitacin B.

[0632] In preferred embodiments of the method to manufacture a HSA nanocamer system as described herein, the molar ratio of the immunomodulatory drug to HSA is comprised between 1 and 30.

[0633] In preferred embodiments of the method to manufacture a HSA nanocamer system as described herein, the immunomodulatory drug is covalently bound to said HSA via a cleavable drug linker. In preferred embodiments of the method to manufacture a HSA nanocarrier system as described herein, the immunomodulatory drug is covalently bound to said HSA via a non-cleavable drug linker. In preferred embodiments of the method to manufacture a HSA nanocamer system as described herein, the immunomodulatory drug is covalently bound to said HSA via a drug linker comprising a thiol-reactive functional group. Preferably, the drug linker is selected from pyridinyldithio-ethoxy-carbonyl, or mc-vc-pabc linker (maleimidocaproyl (me) - valine-citrulline (vc) -para-amino benzyloxycarbonyl (PABC).

[0634] In preferred embodiments of the method to manufacture a HSA nanocamer system as described herein, the drug linker is selected from the group consisting of pyridinyldithio-ethoxy-carbonyl-group, maleimide, mc-vc-pabc linker, thiosulfonate linker, hydrazide-maleimide linker, iodoacetamide linker, and methanethiosulfonate linker.

[0635] In preferred embodiments of the method to manufacture a HSA nanocamer system as described herein, the interconnecting molecule in step ii. comprises polyethylene glycol with a number of ethylene glycol repeating units between 2 and 10.

[0636] In preferred embodiments of the method to manufacture a HSA nanocamer system as described herein, the interconnecting molecule in step ii. is selected from NHS-DBCO, NHS-PEGn-DBCO, BCN-Endo-NHS, BCN-Endo-PEGn-NHS, NHS-DIBO, NHS-PEGn-DIBO, NHS-DIFO, NHS-PEGn-DIFO, NHS-BCN, NHS- PEGn-BCN, NHS-TCO, NHS-PEGn-TCO, NHS-alkyne, NHS-PEGn-alkyne, NHS- azide, NHS-PEGn-Azide, STP-DBCO, STP-PEGn-DBCO, BCN-Endo-STP, BCN- Endo-PEGn-STP, STP-DIBO, STP-PEGn-DIBO, STP-DIFO, STP-PEGn-DIFO, STP-BCN, STP-PEGn-BCN, STP-TCO, STP-PEGn-TCO, STP-alkyne, STP- PEGn-alkyne, STP-azide, STP-PEGn-Azide, TFP-DBCO, TFP-PEGn-DBCO, BCN-Endo-TFP, BCN-Endo-PEGn-TFP, TFP-DIBO, TFP-PEGn-DIBO, TFP-DIFO, TFP-PEGn-DIFO, TFP-BCN, TFP-PEGn-BCN, TFP-TCO, TFP-PEGn-TCO, TFP- alkyne, TFP-PEGn-alkyne, TFP-azide, TFP-PEGn-Azide, PTP-DBCO, PTP-PEGn- DBCO, BCN-Endo-PTP, BCN-Endo-PEGn-PTP, PTP-DIBO, PTP-PEGn-DIBO, PTP-DIFO, PTP-PEGn-DIFO, PTP-BCN, PTP-PEGn-BCN, PTP-TCO, PTP-PEGn- TCO, PTP-alkyne, PTP-PEGn-alkyne, PTP-azide, PTP-PEGn-Azide, NPC-DBCO, NPC-PEGn-DBCO, BCN-Endo-NPC, BCN-Endo-PEGn-NPC, NPC-DIBO, NPC- PEGn-DIBO, NPC-DIFO, NPC-PEGn-DIFO, NPC-BCN, NPC-PEGn-BCN, NPC- TCO, NPC-PEGn-TCO, NPC-alkyne, NPC-PEGn-alkyne, NPC-azide, NPC-PEGn- Azide, NCS-azide, NCS-PEGn-azide, NCS-alkyne, NCS-PEGn-alkyne, NCS- DBCO, NCS-PEGn-DBCO, BCN-Endo-NCS, BCN-Endo-PEGn-NCS, NCS-DIBO, NCS-PEGn-DIBO, NCS-DIFO, NCS-PEGn-DIFO, NCS-BCN, NCS-PEGn-BCN, DBCO-COOH, DBCO-PEGn-COOH, BCN-Endo-COOH, BCN-Endo-PEGn- COOH, BCN-COOH, BCN-PEGn-COOH, DIBO-COOH, DIBO-PEGn-COOH, DIFO-COOH, DIFO-PEGn-COOH, Alkyne-COOH, and Alkyne-PEGn-COOH, wherein n represents the number of ethylene glycol repeating units between 2 and 10.

[0637] In even more preferred embodiments of the method to manufacture a HSA nanocamer system as described herein, the interconnecting molecule in step ii. is selected from NHS-PEGn-DBCO, Endo-BCN-PEGn-NHS, NHS-PEGn-DIBO, NHS- PEGn-DIFO, NHS-PEGn-BCN, NHS-DBCO, Amine-PEGn-DBCO, Amine-DBCO, Acid-PEGn-DBCO, Acid-DBCO, STP-PEGn-DBCO, STP-DBCO, TFP-DBCO, TFP- PEGn-DBCO, PTP-PEGn-DBCO, and PTP-DBCO, wherein n represents the number of ethylene glycol repeating units between 2 and 10.

[0638] In preferred embodiments of the method to manufacture a HSA nanocamer system as described herein, the interconnecting molecule in step ii. comprises an azide-reactive group selected from DBCO, Endo-BCN, DIBO, DIFO, and BCN.

[0639] In preferred embodiments of the method to manufacture a HSA nanocamer system as described herein, the HSA is labeled with a fluorescent dye emitting fluorescence in a range comprised between 400 and 850 nm.

[0640] In preferred embodiments of the method to manufacture a HSA nanocamer system as described herein, the HSA is labeled with a fluorescent dye via a maleimide or an NHS-ester.

[0641] In a preferred embodiment, the method to manufacture a HSA nanocarrier system as described herein, comprises the following steps: i.) providing monomolecular native HSA, wherein the monomolecular native HSA is optionally labeled with a fluorescent dye; i.1 ) subjecting the HSA labeled with a fluorescent dye maleimide to a ring-opening hydrolysis by adding a buffer at a pH above 9. ii.) attaching an interconnecting molecule to the HSA; iii.) covalently binding of a plurality of monomannose or dimannose or trimannose moieties to the interconnecting molecule to obtain mannosylated HSA; iv.) denaturing of the mannosylated HSA obtained at step iii.; v.-a) covalently binding of at least one immunomodulatory drug to said denatured mannosylated HSA, wherein the one or more immunomodulatory drugs are attached to a drug linker comprising a thiol-reactive functional group; v.-b) capping of unreacted thiols, preferably with N-ethylmaleimide; v.-c) washing the denatured nanocarrier system obtained in step v.-b; vi.) backfolding of the denatured nanocarrier system via rapid dilution procedure; vii.) obtaining a monomolecular HSA nanocamer system wherein the at least one immunomodulatory drug is not doxorubicin.

[0642] In a preferred embodiment, the method to manufacture a HSA nanocarrier system as described herein, comprises the following steps: i.) providing monomolecular native HSA, wherein the monomolecular native HSA is optionally labeled with a fluorescent dye; i.1 ) subjecting the HSA labeled with a fluorescent dye maleimide to a ring-opening hydrolysis by adding a buffer at a pH above 9. ii.) attaching an interconnecting molecule to the HSA; iii.) covalently binding of a plurality of monomannose or dimannose or trimannose moieties to the interconnecting molecule to obtain mannosylated HSA; iv.) denaturing of the mannosylated HSA obtained at step iii.; v.-a) covalently binding of at least one immunomodulatory drug selected from

[0643] TLR agonist or STAT3 inhibitor to said denatured mannosylated HSA, wherein the one or more immunomodulatory drugs are attached to a drug linker comprising a thiol-reactive functional group; v.-b) capping of unreacted thiols, preferably with N-ethylmaleimide; v.-c) washing the denatured nanocarrier system obtained in step v.-b; vi.) backfolding of the denatured nanocarrier system via rapid dilution procedure; vii.) obtaining a monomolecular HSA nanocarrier system.

[0644] Detailed description of the Invention

[0645] The present invention provides a novel nanocarrier system based on human serum albumin (HSA) to target certain liver cells for immunotherapy to treat cancer, and other diseases affecting liver function and liver structure, such as liver fibrosis.

[0646] The novel nanocarrier system comprises HSA, a plurality of monomannose moieties, dimannose moieties, or trimannose moieties, such as a trimannose (TM), and at least one immunomodulatory drug selected from a TLR agonist or a STAT3 inhibitor covalently bound to said HSA. The at least one immunomodulatory drug is preferably linked to HSA via a cleavable, traceless linker or a non-cleavable linker.

[0647] The inventive nanocarrier system has the advantage that the drug cargo is specifically and efficiently delivered via active targeting to liver cells expressing surface mannose receptors, such as CD209 or CD206 or homologues thereof in the case of a trimannose. Moreover, the inventive nanocarrier system has the advantage over the prior art that the drug-cargo is covalently linked to HSA via a linker, thereby releasing the drug cargo at the liver target site. Drug nanoparticle systems of the prior art (e.g. Biomacromolecules 2020, 21 , 3704-3712) comprising a stable showed a lower potency in vitro compared to the free drug.

[0648] In contrast to free HSA, which distributes in high concentrations in the blood stream (see Theranostics 2017; 7(15):3667-3689), the inventors could show that the inventive nanocarrier system rapidly clears from the bloodstream, and is selectively uptaken into the liver, independent of any cargo. To this extent, small blood samples (50 pL) were collected from mice at 0.1 h and 24 h after injection with TM-HSA conjugates, and plasma was analyzed using fluorescence correlation spectroscopy (FCS) to measure particle size and concentration. In control experiments, plasma samples from mouse blood incubated with TM-HSA- TLR7 / 8a at a comparable concentration (estimated initial blood concentration «230 nM) showed that HSA maintained high concentrations immediately after injection (238 ± 8 nM) with detectable levels (40 ± 6 nM) persisting at 24 h (Figure 34B). In contrast, TM-HSA conjugates — including TM-HSA, TM-HSA-Benzyl, and TM-HSA- TLR7 / 8a — exhibited rapid clearance, with concentrations dropping from 1-6 nM shortly after injection to undetectable levels at 24 h post-injection of these conjugates. The plasma control sample, TM-HSA-TLR7 / 8a incubated ex vivo in whole blood, showed no such decrease in concentration, ruling out adsorptive interactions with blood components during plasma generation.

[0649] MS imaging demonstrated that while HSA distributed throughout the body with a trend for higher accumulation in the liver (Figure 34A), TM-HSA conjugates showed direct accumulation mainly in the liver post-injection (Figure 34A). Ex vivo fluorescence analysis of organs highlighted significant differences in organ enrichment between HSA and TM-HSA conjugates (Figure 34D and E). HSA was enriched in the heart 24 h post-injection, confirming its prolonged presence in the bloodstream. Additionally, HSA showed higher accumulation in the lungs and kidneys compared to TM-HSA conjugates, indicating renal clearance of HSA. Conversely, TM-HSA conjugates exhibited minimal accumulation in these organs, verifying enhanced selective liver targeting in vivo. TM-HSA conjugates were also observed in the spleen; however, the difference from HSA spleen uptake was not statistically significant. The ratio of liver fluorescence intensity to total body intensity confirmed significantly enhanced liver-specific targeting for TM-HSA bioconjugates, indicating enhanced organ specificity when using TM as a targeting unit (Figure 34). Moreover, the attached cargo did not impact the biodistribution of the TM-HSA nanocarrier. Thus, an enhanced specificity and binding affinity to immune cells ex vivo and selective uptake in vivo into the live is achieved with the inventive HSA nanocamer system over the prior art systems.

[0650] Direct accumulation of TM-HSA conjugates in the liver, but not in tumor, was also observed in tumor mouse model (see Figure 34).

[0651] Further, the HSA carrier of the inventive nanocarrier system reduces non-specific, passive uptake in vitro compared to synthetic polymer nanoparticles of the prior art (e.g. Biomacromolecules 2020, 21 , 3704-3712).

[0652] In an exemplary synthesis procedure, the lysine residues of native HSA are modified using NHS-chemistry to attach DBCO (Dibenzoazacyclooctyne) linkers to the protein surface. The glycolytic targeting structure, e.g. trimannose (TM), is synthesized with an azide as functional group to click in a strain-promoted copper free azide alkyne click reaction to the DBCO linkers. The mannosylated HSA is then completely denatured including the reduction of the native disulfides. The resulting free thiols react with a thiol-reactive functional group attached to at least one immunomodulatory drug of interest. Preferred thiol-reactive functional groups to attach the immunomodulatory drug are selected from a pyridinyldithio-ethoxy- carbonyl-group or a maleimide. Unreacted thiols on HSA are capped with a capping reagent, such as A / -ethylmaleimide. Afterwards, all reactive substances are washed out and the conjugated HSA protein is folded via rapid dilution procedure, thereby leading to an a-helix-rich globular structure very similar to the native conformation based on CD measurements. The synthesis procedures allow obtaining nanocamer preparations containing monomolecular HSA-nanocamers and only less than 8% aggregates or multi-HSA nanocarriers based on FCS measurements.

[0653] In vitro assays showed excellent uptake of this novel nanocamer system compared to suitable controls by CD206-transduced CHO-cells (Figures 10-11 ), GM-CSF differentiated BMDC (Figures 12-15, and 29), FLT3L differentiated BMDC (Figures 17-19), liver NPC cells (Figures 12, and 25-27), and spleen cells (Figures 20-24) in 2D- / 7? vitro cell uptake studies. These experiments also showed no immune stimulatory effect by the carrier itself or its substructures without the drug cargo. Moreover, performed experiments showed immune stimulation of antigen presenting cells (Figures 13 - 20, 22 - 27).

[0654] Moreover, TM-HSA nanocamers loaded with Cucurbitacin B were able to induce phenotype-repolarization of M2-type BMDM (Figure 28). Uptake experiments with HSA-nanocarriers preincubated with native and heat- inactivated mouse serum demonstrated that uptake is not significantly decreased indicating that no major protein corona is formed in presence of serum, which could hamper drug delivery (Figures 14, 29). This is further supported by FCS experiments showing no major increase in hydrodynamic radii of cargo loaded HSA nanocarrier upon preincubation with blood plasma (Figure 7).

[0655] TLR7 / 8-Agonist loaded HSA nanocarrier, in contrast to unloaded or decoy loaded HSA nanocarriers, showed equal to superior immune stimulation compared to equimolar small molecule treatment which is demonstrated by FACS analysis of surface activation markers (CD86, MHCII) of respective immune cells upon nanocarrier treatment (Figure 13, 14, 17-20, and 22-27) and by T-cell proliferation assay (Figure 16).

[0656] Human Serum Albumin (HSA), the biopolymeric carrier material, is biocompatible, biodegradable, has low immunogenicity and is FDA approved in nanoparticle formulations like Abraxane® (ca. 140 nm). HSA is a well-known transportation protein, is ubiquitous in blood plasma, comprises natural, non-toxic monomers; and has low membrane permeability.

[0657] Native HSA has 35 cysteine (-SH) residues (including disulfide bridges), 59 lysine (-NH2) residues, and 100 aspartic / glutamic acid (-COOH) residues.

[0658] The term “monomolecular mannosylated HSA nanocarrier system” as used herein refers to a nanoparticle comprising one HSA, a plurality of mannose-based targeting structures, and an immunomodulatory drug of choice, all covalently linked or conjugated. The HSA in the nanocarrier has preferably an a-helix rich, globular conformation.

[0659] The term “HSA nanocarrier system” or “nanocarrier system” as used herein refers to a nanoparticle comprising one HSA, a single or a plurality of mannose-based targeting structures, and at least one immunomodulatory drug, wherein the mannose-based targeting structures and the at least one immunomodulatory drug are covalently linked or conjugated to HSA. The mannose-based targeting structures and the at least one immunomodulatory drug can either be directly bound to the HSA or via a linker / spacer. However, the mannose-based targeting structures are not coupled to the at least one immunomodulatory drug and the at least one immunomodulatory drug is not coupled to the mannose-based targeting structures. Therefore, the mannose-based targeting structures and the at least one immunomodulatory drug are covalently linked or conjugated to HSA such that there is no interaction between the mannose-based targeting structures and the at least one immunomodulatory drug. The HSA in the nanocarrier system has preferably an a-helix rich, globular conformation.

[0660] The term “monomolecular HSA nanocarrier system” as used herein refers to a HSA nanocarrier system as described herein comprising a single HSA molecule in its monomeric form, without covalent dimers, trimers, or other higher order oligomers.

[0661] The term "ring-opening hydrolysis" refers to a hydrolysis reaction to open a maleimide ring occurring at high pH (above 9). The ring-opening reaction is irreversible and leads to stable products.

[0662] Fluorescent dyes to trace the HSA nanocarrier system

[0663] According to one aspect of the invention, the HSA nanocarrier system is traced by conjugating the HSA molecule with a fluorescent dye. Preferred dyes are water soluble dyes emitting in the range 400 - 850 nm (VIS / NIR range). Preferred dyes are sulfocyanine dyes, or other derivatives of dyes of the coumarin, rhodamine, cyanine or xanthene family.

[0664] Sulfo-Cyanine5-Maleimide (Mal-SCy5) is a water soluble, hydrophilic dye similar to Cy5® maleimide (Cy5® maleimide analog) for protein labeling, including labeling of antibodies. Labeled proteins can be easily separated from unreacted dye by gel filtration, spin column purification, dialysis, electrophoresis or chromatography. Cyanine5-Maleimide is a mono-reactive dye which selectively couples with thiol groups (for example, with cysteines in peptides and proteins) to give labeled conjugates. Cyanine5 is an analog of Cy5® (2-[5-[1-(5-Carboxypentyl)-1 ,3- dihydro-3,3-dimethyl-5-sulfo-2H-indol-2-ylidene]-1 ,3-pentadienyl]-1-ethyl-3,3- dimethyl-5-sulfo-3H-indolium inner salt), a common fluorophore which is compatible with various instrumentations like microscopes, imagers, and fluorescence readers.

[0665] Mannose moiety The term "mannose moiety" as used herein refers to an antennary molecular structure comprising one or more terminal mannose saccharides, wherein the reducing end of each mannose saccharide is functionalized with one and the same backbone forming linker comprising a functional group, such as a terminal azide group, for covalent attachment to the nanocamer for instance via an azide-alkyne- click-reaction. In case of more than one terminal mannose saccharide, the linker is a branched molecule connecting each terminal mannose saccharide with the functional group as focal point, thereby forming a dendron-like structure. Each terminal mannose saccharide consists of one or more mannopyranose units, wherein, when the terminal mannose saccharide comprises more than one mannopyranose unit, these mannopyranose units are bound to each other via a glycosidic bond (e.g. an a-(1 ->3)- and / or an a-(1 ->6)-glycosidic bond). Exemplarily, the monosaccharide targeting structure ManpNs consists of a single a-O-mannopyranoside unit and a tetraethylene glycol spacer, which contains an azide function at the terminal position. Both parts are connected via a 1 ,4-disubstituted-1 ,2,3-triazole, with position 1 connected to the spacer and position 4 to a glycosylated oxo-methylene group. The trisaccharide targeting structure ManpsNs (TM) comprises a central a-O-mannopyranoside unit carrying the same spacer aglycon as described for ManpNs, and two further mannopyranosyl residues attached to the central unit via an a-(1 ->3)- and an a- (1 ->6)-glycosidic bond (i.e. Man<z1 -3[Man<z1 -6]Man<z), respectively. The monosaccharide carrying dendron-like targeting structure (Manp)3N3 contains three a-O-mannopyranoside units each glycosylated to a triazole tetraethylene glycol spacer, as the ones already described. The spacers themselves are connected via a terminal amino group as part of an amide bond to a central structure, containing three ethylene units branching out from the TRIS-based core. The amino group of the core is connected via an amide bond to a triethylene glycol-based linker, whose acid function results from a Michael addition with tertbutyl acrylate, and which carries the terminal azide group for attachment to the nanocarrier. The trisaccharide carrying dendron-like targeting structure (Manps^Ns contains three trimannose units, as described for ManpsNs, each glycosylated in the same way as described for (Manp)3N3. A preferred "mannose moiety " for the HSA nanocarrier system disclosed herein is selected from the group consisting of the described targeting structures ManpNs, ManpsNs, (Manp)sN3, and (Manp3)sN3 (Figure 1 B). The term “monomannose moiety” refers to a mannose moiety comprising of at least one terminal single a-O-mannopyranoside unit (e.g. ManpNs or (Manp^Ns) and is devoid of a mannose oligomer.

[0666] The term “dimannose moiety” refers to a mannose moiety comprising of at least one terminal a-O-dimannopyranoside unit, the mannopyranoside units bound to each other via a glycosidic bond (e.g. an a-(1 ->3)- and / or an a-(1 ->6)-glycosidic bond) and which is devoid of a monomannose moiety or a mannose oligomer consisting of more than two mannose units.

[0667] The term “trimannose moiety” refers to a mannose moiety comprising of at least one terminal a-O- trimannopyranoside unit (e.g. ManpsNs or and (Manps^Ns), the mannopyranoside units bound to each other via a glycosidic bond (e.g. an a-(1 ->3)- and / or an a-(1 ->6)-glycosidic bond) and which is devoid of a monomannose moiety, a dimannose moiety or a mannose oligomer consisting of more than three mannose units.

[0668] The term “plurality of monomannose moieties, dimannose moieties, or trimannose moieties” or synonymously “plurality of monomannose or dimannose or trimannose moieties” or synonymously “plurality of mannose moieties” may include a plurality of monomannose moieties, dimannose moieties, and trimannose moieties, a plurality of monomannose moieties, a plurality of dimannose moieties, a plurality of trimannose moieties, a plurality of monomannose moieties and dimannose moieties, a plurality of monomannose moieties and trimannose moieties, or a plurality of dimannose moieties and trimannose moieties.

[0669] The biological targeting unit mannose, and in particular trimannose (TM), binds to C-type lectin receptors, namely CD206 (MMR) and CD209 (DC-SIGN) and respective homologues (Zhang F, et al., 2014. DC-SIGN, DC-SIGNR and LSECtin: C-type lectins for infection. Int Rev Immunol. 33(1 ):54-66; Boskovich et al., 2006. Protein Structure and Folding 281 (13) P8780-8787; Gupta et al., 2012. Animal Lectins: Form, Function and Clinical Applications, 773-798.). MMR is mainly expressed on M2-polarized macrophages, which are anti-inflammatory and with pro-tumorous phenotype, immature dendritic cells as well as specialized liver endothelial cells LSECs. DC-SIGN is mainly expressed on dendritic cells.

[0670] Various mannose moieties of different length and structure showed similar uptake behavior in the inventive HSA nanocarriers (see Figures 31 and 32). Therefore, all mannose moieties described herein are suitable for the inventive HSA nanocarriers.

[0671] The term "molar ratio mannose:HSA" or synonymously “molar mannose:HSA ratio” or synonymously “molar ratio of mannose to HSA” refers to the number of molecules of mannose loaded on one HSA molecule.

[0672] Linkage of mannose to HSA

[0673] The plurality of mannose moieties is linked to HSA by using click chemistry, preferably by copper free azide-alkyne click chemistry, thereby forming mannosylated HSA.

[0674] Linker length and linker type do not affect the properties of the inventive HSA nanocarriers (see Figure 36) for different mannose moieties. Thus, any linker may be suitable for linking the plurality of mannose moieties to HSA.

[0675] Preferred linkers reacting with azide are selected from NHS-DBCO, NHS-PEGn- DBCO, BCN-Endo-NHS, BCN-Endo-PEGn-NHS, NHS-DIBO, NHS-PEGn-DIBO, NHS-DIFO, NHS-PEGn-DIFO, NHS-BCN, NHS-PEGn-BCN, NHS-TCO, NHS- PEGn-TCO, NHS-alkyne, NHS-PEGn-alkyne, NHS-azide, NHS-PEGn-Azide, STP-DBCO, STP-PEGn-DBCO, BCN-Endo-STP, BCN-Endo-PEGn-STP, STP- DIBO, STP-PEGn-DIBO, STP-DIFO, STP-PEGn-DIFO, STP-BCN, STP-PEGn- BCN, STP-TCO, STP-PEGn-TCO, STP-alkyne, STP-PEGn-alkyne, STP-azide, STP-PEGn-Azide, TFP-DBCO, TFP-PEGn-DBCO, BCN-Endo-TFP, BCN-Endo- PEGn-TFP, TFP-DIBO, TFP-PEGn-DIBO, TFP-DIFO, TFP-PEGn-DIFO, TFP- BCN, TFP-PEGn-BCN, TFP-TCO, TFP-PEGn-TCO, TFP-alkyne, TFP-PEGn- alkyne, TFP-azide, TFP-PEGn-Azide, PTP-DBCO, PTP-PEGn-DBCO, BCN-Endo- PTP, BCN-Endo-PEGn-PTP, PTP-DIBO, PTP-PEGn-DIBO, PTP-DIFO, PTP- PEGn-DIFO, PTP-BCN, PTP-PEGn-BCN, PTP-TCO, PTP-PEGn-TCO, PTP- alkyne, PTP-PEGn-alkyne, PTP-azide, PTP-PEGn-Azide, NPC-DBCO, NPC- PEGn-DBCO, BCN-Endo-NPC, BCN-Endo-PEGn-NPC, NPC-DIBO, NPC-PEGn- DIBO, NPC-DIFO, NPC-PEGn-DIFO, NPC-BCN, NPC-PEGn-BCN, NPC-TCO, NPC-PEGn-TCO, NPC-alkyne, NPC-PEGn-alkyne, NPC-azide, NPC-PEGn-Azide, NCS-azide, NCS-PEGn-azide, NCS-alkyne, NCS-PEGn-alkyne, NCS-DBCO, NCS-PEGn-DBCO, BCN-Endo-NCS, BCN-Endo-PEGn-NCS, NCS-DIBO, NCS- PEGn-DIBO, NCS-DIFO, NCS-PEGn-DIFO, NCS-BCN, NCS-PEGn-BCN, DBCO- COOH, DBCO-PEGn-COOH, BCN-Endo-COOH, BCN-Endo-PEGn-COOH, BCN- COOH, BCN-PEGn-COOH, DIBO-COOH, DIBO-PEGn-COOH, DIFO-COOH, DIFO-PEGn-COOH, Alkyne-COOH, and Alkyne-PEGn-COOH, wherein

[0676] DBCO (or DIBAC or ADIBO) stands for dibenzoazacyclooctyne, Endo-BCN for endo-bicyclo[6.1 ,0]non-4-yn-9-yl, DIBO for dibenzocyclooctyne, DIFO for difluorocyclooctyne-CFh-COOH, BCN for bicyclo[6.1 .0]nonyne, NHS for N- Hydroxysuccinimide, STP for Sulfo-4-succinimidyl 4-(p-maleimidophenyl)butyrate, TFP for 2,3,5,6-Tetrafluorophenyl ester, PTP for Pentafluorophenyl ester, also PFP, and NPC for N-Phenylcarbonate ester; .

[0677] NHS-PEGn-DBCO refers to a dibenzoazacyclooctyne polyethylene glycol NHS- ester, wherein n represents the number of ethylene glycol repeating units. Preferably, n is an integer selected between 1 and 50, more preferably between 1 and 20, more preferably between 2 and 10, more preferably between 2 and 8. In another embodiment, n is 3. In a preferred embodiment, n is 4. In another embodiment, n is 6. In another embodiment, n is 12. In another embodiment, n is 24.

[0678] The term “mannosylated HSA” as used herein refers to a conjugate of one or a plurality of mannose moieties and HSA. The HSA may be labeled with a fluorescent dye.

[0679] Unreacted thiols on HSA at step v. can be capped with any maleimide, preferably small, n-substituted maleimides. Preferably, unreacted thiols on HSA are capped with N-Ethylmaleimide

[0680] The term “linker” as used herein encompasses molecular fragments capable of connecting the reducing-end monosaccharide of the mannose moiety of the plurality of mannose moieties with a reactive group of HSA, optionally by binding to at least one interconnecting molecule. Thus, the function of the linker perse or together with the interconnecting molecule is to establish, keep and / or bridge a special distance between the reducing-end mannose and HSA. More specifically, one extremity of the linker is connected to the exocyclic oxygen atom at the anomeric center of the reducing-end mannose and the other extremity is connected via the functional group, e.g. an azide with the interconnecting molecule, or directly with HSA.

[0681] As used herein, the term “interconnecting molecule” refers to a bifunctional molecule containing functional group X and functional group Y, wherein functional group X is capable of reacting with the terminal functional group on the linker and the functional group Y is capable of reacting with a functionality present on HSA, preferably a primary amino group, such as an s-amino group of lysine. A preferred interconnecting molecule used in the inventive nanocamer system is NHS-PEGn- DBCO, particularly, NHS-PEG4-DBCO.

[0682] The linker may be a heterobifunctional interconnecting molecule comprising an active ester and a terminal alkyne as functional groups. Suitable active esters are NHS (N-Hydroxysuccinimide), STP (Sulfo-4-succinimidyl 4-(p- maleimidophenyl)butyrate), TFP (2,3,5,6-Tetrafluorophenyl ester), PTP (Pentafluorophenyl ester, also PFP), and NPC (N-Phenylcarbonate ester); Suitable alkynes are DBCO, Endo-BCN, BCN, DIBO, DIFO, and propargyl.

[0683] Thus, in a preferred embodiment, the HSA-nanocarrier system for drug delivery comprises:

[0684] A) a human serum albumin (HSA);

[0685] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA via a heterobifunctional interconnecting molecule comprising an active ester and a terminal alkyne as functional groups;

[0686] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering.

[0687] In another preferred embodiment, the HSA-nanocarrier system for drug delivery comprises:

[0688] A) a human serum albumin (HSA);

[0689] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA via a heterobifunctional interconnecting molecule comprising an active ester and an azide as functional groups;

[0690] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering.

[0691] In another preferred embodiment, the HSA-nanocarrier system for drug delivery comprises: A) a human serum albumin (HSA);

[0692] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA via a heterobifunctional interconnecting molecule comprising an amino group and an alkyne as functional groups;

[0693] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering.

[0694] In another preferred embodiment, the HSA-nanocarrier system for drug delivery comprises:

[0695] A) a human serum albumin (HSA);

[0696] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA via a heterobifunctional interconnecting molecule comprising an Michael acceptor and an alkyne as functional groups;

[0697] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering.

[0698] In another preferred embodiment, the HSA-nanocarrier system for drug delivery comprises:

[0699] A) a human serum albumin (HSA);

[0700] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA via a heterobifunctional interconnecting molecule comprising an Michael acceptor and an azide as functional groups;

[0701] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering.

[0702] In another preferred embodiment, the HSA-nanocarrier system for drug delivery comprises:

[0703] A) a human serum albumin (HSA); B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA via a heterobifunctional interconnecting molecule comprising an Michael acceptor and a carboxylic acid as functional groups;

[0704] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering.

[0705] In another preferred embodiment, the HSA-nanocarrier system for drug delivery comprises:

[0706] A) a human serum albumin (HSA);

[0707] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA via a heterobifunctional interconnecting molecule comprising two functional groups X and Y;

[0708] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering; wherein the functional group X Is selected from activated ester, carboxylic acid, isocyanate, isothiocyanate, amino group, and maleimide; and wherein the functional group Y is selected from cyclooctyne, alkyne, azide, trans cyclooctene, and carboxylic acid.

[0709] In another preferred embodiment, the HSA-nanocarrier system for drug delivery comprises:

[0710] A) a human serum albumin (HSA);

[0711] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA via a heterobifunctional interconnecting molecule comprising two functional groups X and Y;

[0712] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering; wherein the functional group X Is selected from NHS (N-Hydroxysuccinimide), STP (Sulfo-4-succinimidyl 4-(p-maleimidophenyl)butyrate), TFP (2, 3,5,6- Tetrafluorophenyl ester), PTP (Pentafluorophenyl ester, also PFP), and NPC (N- Phenylcarbonate ester); and wherein the functional group Y is selected from DBCO, Endo-BCN, BCN, DIBO, DIFO, and propargyl.

[0713] In another preferred embodiment, the HSA-nanocarrier system for drug delivery comprises:

[0714] A) a human serum albumin (HSA);

[0715] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA via a linker,

[0716] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering; and wherein said linker is selected from NHS-DBCO, NHS-PEGn-DBCO, BCN-Endo- NHS, BCN-Endo-PEGn-NHS, NHS-DIBO, NHS-PEGn-DIBO, NHS-DIFO, NHS- PEGn-DIFO, NHS-BCN, NHS-PEGn-BCN, NHS-TCO, NHS-PEGn-TCO, NHS- alkyne, NHS-PEGn-alkyne, NHS-azide, NHS-PEGn-Azide, STP-DBCO, STP- PEGn-DBCO, BCN-Endo-STP, BCN-Endo-PEGn-STP, STP-DIBO, STP-PEGn- DIBO, STP-DIFO, STP-PEGn-DIFO, STP-BCN, STP-PEGn-BCN, STP-TCO, STP- PEGn-TCO, STP-alkyne, STP-PEGn-alkyne, STP-azide, STP-PEGn-Azide, TFP- DBCO, TFP-PEGn-DBCO, BCN-Endo-TFP, BCN-Endo-PEGn-TFP, TFP-DIBO, TFP-PEGn-DIBO, TFP-DIFO, TFP-PEGn-DIFO, TFP-BCN, TFP-PEGn-BCN, TFP- TCO, TFP-PEGn-TCO, TFP-alkyne, TFP-PEGn-alkyne, TFP-azide, TFP-PEGn- Azide, PTP-DBCO, PTP-PEGn-DBCO, BCN-Endo-PTP, BCN-Endo-PEGn-PTP, PTP-DIBO, PTP-PEGn-DIBO, PTP-DIFO, PTP-PEGn-DIFO, PTP-BCN, PTP- PEGn-BCN, PTP-TCO, PTP-PEGn-TCO, PTP-alkyne, PTP-PEGn-alkyne, PTP- azide, PTP-PEGn-Azide, NPC-DBCO, NPC-PEGn-DBCO, BCN-Endo-NPC, BCN- Endo-PEGn-NPC, NPC-DIBO, NPC-PEGn-DIBO, NPC-DIFO, NPC-PEGn-DIFO, NPC-BCN, NPC-PEGn-BCN, NPC-TCO, NPC-PEGn-TCO, NPC-alkyne, NPC- PEGn-alkyne, NPC-azide, NPC-PEGn-Azide, NCS-azide, NCS-PEGn-azide, NCS- alkyne, NCS-PEGn-alkyne, NCS-DBCO, NCS-PEGn-DBCO, BCN-Endo-NCS, BCN-Endo-PEGn-NCS, NCS-DIBO, NCS-PEGn-DIBO, NCS-DIFO, NCS-PEGn- DIFO, NCS-BCN, NCS-PEGn-BCN, DBCO-COOH, DBCO-PEGn-COOH, BCN- Endo-COOH, BCN-Endo-PEGn-COOH, BCN-COOH, BCN-PEGn-COOH, DIBO- COOH, DIBO-PEGn-COOH, DIFO-COOH, DIFO-PEGn-COOH, Alkyne-COOH, and Alkyne-PEGn-COOH, wherein n represents the number of ethylene glycol repeating units between 2 and 10. In another preferred embodiment, the HSA-nanocarrier system for drug delivery comprises:

[0717] A) a human serum albumin (HSA);

[0718] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA via a linker,

[0719] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering; and wherein said linker is selected from NHS-DBCO, NHS-PEGn-DBCO, BCN-Endo- NHS, BCN-Endo-PEGn-NHS, NHS-DIBO, NHS-PEGn-DIBO, NHS-DIFO, NHS- PEGn-DIFO, NHS-BCN, NHS-PEGn-BCN, NHS-alkyne, NHS-PEGn-alkyne, NHS- azide, NHS-PEGn-Azide, STP-DBCO, STP-PEGn-DBCO, BCN-Endo-STP, BCN- Endo-PEGn- STP, STP-DIBO, STP-PEGn-DIBO, STP-DIFO, STP-PEGn-DIFO, STP-BCN, STP-PEGn-BCN, STP-alkyne, STP-PEGn-alkyne, STP-azide, STP- PEGn-Azide, TFP-DBCO, TFP-PEGn-DBCO, BCN-Endo-TFP, BCN-Endo-PEGn- TFP, TFP-DIBO, TFP-PEGn-DIBO, TFP-DIFO, TFP-PEGn-DIFO, TFP-BCN, TFP- PEGn-BCN, TFP-alkyne, TFP-PEGn-alkyne, TFP-azide, TFP-PEGn-Azide, PTP- DBCO, PTP-PEGn-DBCO, BCN-Endo-PTP, BCN-Endo-PEGn- PTP, PTP-DIBO, PTP-PEGn-DIBO, PTP-DIFO, PTP-PEGn-DIFO, PTP -BCN, PTP-PEGn-BCN, PTP-alkyne, PTP-PEGn-alkyne, PTP-azide, PTP-PEGn-Azide, NPC-DBCO, NPC- PEGn-DBCO, BCN-Endo-NPC, BCN-Endo-PEGn-NPC, NPC-DIBO, NPC-PEGn- DIBO, NPC-DIFO, NPC-PEGn-DIFO, NPC-BCN, NPC-PEGn-BCN, NPC-alkyne, NPC-PEGn-alkyne, NPC-alkyne, NPC-PEGn-alkyne, NPC-azide, and NPC-PEGn- Azide, wherein n represents the number of ethylene glycol repeating units between 2 and 10.

[0720] In another preferred embodiment, the HSA-nanocarrier system for drug delivery comprises:

[0721] A) a human serum albumin (HSA);

[0722] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA via a linker,

[0723] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering; and wherein said linker is selected from NHS-DBCO, NHS-PEGn-DBCO, BCN-Endo- NHS, BCN-Endo-PEGn-NHS, NHS-DIBO, NHS-PEGn-DIBO, NHS-DIFO, NHS- PEGn-DIFO, NHS-BCN, NHS-PEGn-BCN, NHS-azide, NHS-PEGn-Azide, STP- DBCO, STP-PEGn-DBCO, BCN-Endo-STP, BCN-Endo-PEGn- STP, STP-DIBO, STP-PEGn-DIBO, STP-DIFO, STP-PEGn-DIFO, STP-BCN, STP-PEGn-BCNSTP- azide, STP-PEGn-Azide, TFP-DBCO, TFP-PEGn-DBCO, BCN-Endo-TFP, BCN- Endo-PEGn- TFP, TFP-DIBO, TFP-PEGn-DIBO, TFP-DIFO, TFP-PEGn-DIFO, TFP-BCN, TFP-PEGn-BCN, TFP-azide, TFP-PEGn-Azide, PTP-DBCO, PTP- PEGn-DBCO, BCN-Endo-PTP, BCN-Endo-PEGn- PTP, PTP-DIBO, PTP-PEGn- DIBO, PTP-DIFO, PTP-PEGn-DIFO, PTP -BCN, PTP-PEGn-BCN, PTP-azide, PTP-PEGn-Azide, NPC-DBCO, NPC-PEGn-DBCO, BCN-Endo-NPC, BCN-Endo- PEGn-NPC, NPC-DIBO, NPC-PEGn-DIBO, NPC-DIFO, NPC-PEGn-DIFO, NPC- BCN, NPC-PEGn-BCN, NPC-azide, and NPC-PEGn-Azide, wherein n represents the number of ethylene glycol repeating units between 2 and 10.

[0724] In another preferred embodiment, the HSA-nanocarrier system for drug delivery comprises:

[0725] A) a human serum albumin (HSA);

[0726] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA via a linker,

[0727] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering; and wherein said linker is selected from NHS-PEGn-DBCO, Endo-BCN-PEGn-NHS, NHS-PEGn-DIBO, NHS-PEGn-DIFO, NHS-PEGn-BCN, NHS-DBCO, Amine-PEGn- DBCO, Amine-DBCO,Acid-PEGn-DBCO, Acid-DBCO, STP-PEGn-DBCO, STP- DBCO, TFP-DBCO, TFP-PEGn-DBCO, PTP-PEGn-DBCO, PTP-DBCO wherein n represents the number of ethylene glycol repeating units between 2 and 10.

[0728] In another preferred embodiment, the HSA-nanocarrier system for drug delivery comprises:

[0729] A) a human serum albumin (HSA);

[0730] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA via a linker, C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering; and wherein said linker is selected from NHS-PEGn-DBCO, NHS-azide, and NHS- PEGn-Azide, wherein n represents the number of ethylene glycol repeating units between 2 and 10.

[0731] Immunomodulatory drug cargo

[0732] The term “immunomodulatory drug” or “immunomodulatory compound” or “immunomodulator” as used herein refers to a small molecule or peptidic inhibitor that affects the functioning of the immune system by increasing or decreasing the immune response.

[0733] Preferred immunomodulatory drugs for the nanocarrier system disclosed herein are small molecules or peptidic inhibitors selected from the group consisting of TLR agonists (e.g.TLR7 / 8-agonist R848 derivative or RGPPP peptide from Pseudostellaria heterophylla), STAT3 inhibitors (e.g. CuB).

[0734] TLR7 / 8 agonists (herein abbreviated as TLR7 / 8_ag) are usually used as adjuvant in cancer vaccination. Suitable TLR7 / 8 agonists used in the present invention are selected from, but not limited to: Resiquimod (R-848), Imiquimod (Aldara, R-837), Vesatolimod (GS-9620), 852A, MEDI9197 (3M-052), ING-8002, ADU-08S, D-2221 , SBI-477, andPRX034.

[0735] Cucurbitacin B (CuB) is a natural substance acting as immunomodulator and cytostatic at low concentration in nanomolar range, i.a. via JAK / STAT inhibition, and as cytotoxic agent at higher concentration in micromolar range, via cytoskeleton interruption.

[0736] Benzylamine can be used as a decoy cargo for the HSA nanocamer system, which shows no biological effect in the applied concentration but still allowed for the loading procedure of the HSA since this alters its 3D-structure significantly. The in vitro data even indicates slight differences in uptake efficiency depending on the cargo that was loaded. The term "molar ratio immunomodulatory drug:HSA" or synonymously “molar immunomodulatory drug:HSA ratio” or synonymously “molar ratio of the immunomodulatory drug to HSA” refers to the number of molecules of immunomodulatory drug loaded on one HSA molecule. The "molar ratio immunomodulatory drug: HSA" depends on different factors such as the chemical structure and size of the immunomodulatory drug, and the resulting loading of the produced nanocarrier system.

[0737] Loading of drug to the nanocarrier system

[0738] In order to link the immunomodulatory drug of choice to HSA, the drug is preferably coupled to a drug linker that is capable of forming a covalent bond with a reactive group (e.g. amino group, thiol group, hydroxyl group, carboxy group etc.) present on the surface of (denatured) mannosylated HSA.

[0739] The term “drug linker” as used herein encompasses molecular fragments capable of connecting the immunomodulatory drug with HSA of mannosylated HSA, optionally by binding to at least one interconnecting molecule. Thus, the function of the drug linker per se or together with the interconnecting molecule is to establish, keep and / or bridge a special distance between the immunomodulatory drug and the HSA of mannosylated HSA. The drug linker is not capable of forming a covalent (or any other type of bond) bond with the mannose-based targeting structure of the mannosylated HSA. More specifically, one extremity of the drug linker is connected to the immunomodulatory drug and the other extremity is connected via a functional group capable of forming a covalent bond with a reactive group (e.g. amino group, thiol group, hydroxyl group, carboxy group etc.) present on the mannosylated HSA.

[0740] Thus, in a preferred embodiment, the HSA-nanocamer system for drug delivery comprises:

[0741] A) a human serum albumin (HSA);

[0742] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0743] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA via a drug linker; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering. The drug linker may be cleavable or non-cleavable (stable) under physiological conditions, depending on the mode of action of the drug. The linker type has no influence on the drug uptake (see Figure 37) as long as no sterical hindrance occurs due to the linker.

[0744] The term “cleavable drug linker”, as used herein, refers to a chemical entity that covalently connects the immunomodulatory drug with HSA of mannosylated HSA, with the ability to undergo specific, controlled cleavage under physiological conditions or in response to specific stimuli, such as pH, enzymes, or reducing agents. This linker allows for the release of the drug from the HSA carrier once the conjugate has reached the target site, thereby ensuring that the drug remains inactive or less active while in circulation and is only activated once it reaches the intended location, such as within a tumor or a specific tissue environment. The cleavable linker serves to optimize the pharmacokinetics, reduce side effects, and improve the therapeutic efficacy of the drug by enhancing its targeted delivery.

[0745] Commonly used enzyme-cleavable linkers that are suitable for the inventive HSA nanocarriers are for example, but not limited to, cathepsin-cleavable peptide linkers (e.g. Val-Cit-PABC, Val-Ala-PABC, and cBu-Cit-PABC), glycosidase-cleavable linkers (e.g. [3-glucuronide linkers, and [3-Galactoside linkers), legumain-sensitive linkers (e.g. Ala-Ala-Asn-PABC linkers), GGFG tetrapeptide linkers, phosphatase-cleavable linkers (e.g. linkers comprising a phosphate or pyrophosphate group), and glutathione-cleavable linkers.

[0746] Suitable glutathione-cleavable linkers are simple disulfide linkers (e.g. bis(2- hydroxyethyl) disulfide, N-succinimidyl 3-(2-pyridyldithio)propionate (SPDP)), self- immolative disulfide linkers (comprising for instance a p-aminobenzyl carbamate, PABC), dithiomaleimide linkers, diselenide linkers, and reduction-sensitive succinimide-thioether linkers, such as N-phenyl maleimide or N-methyl-N-phenylvinylsulfonamide.

[0747] Thus, in a preferred embodiment, the HSA-nanocamer system for drug delivery comprises:

[0748] A) a human serum albumin (HSA);

[0749] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0750] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA via a cleavable drug linker; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, and wherein the cleavable drug linker is selected from cathepsin-cleavable peptide linker, glycosidase-cleavable linker, legumain-sensitive linker, GGFG tetrapeptide linker, phosphatase-cleavable linker, and glutathione-cleavable linker.

[0751] Preferably, the HSA-nanocamer system for drug delivery comprises:

[0752] A) a human serum albumin (HSA);

[0753] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0754] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA via a cleavable drug linker; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, and wherein the cleavable drug linker is a glutathione-cleavable linker.

[0755] Preferably, the drug linker is functionalized with a "thiol-reactive functional group" reacting with free thiols on mannosylated HSA, such that the immunomodulatory drug is covalently bound to a thiol group on mannosylated HSA via the drug linker. Preferred "thiol-reactive functional groups" are selected from the group consisting of pyridinyldithiol-ethoxy-carbonyl-group, maleimide, mc-vc-pabc linker (maleimidocaproyl (me) - valine-citrulline (vc)-para- amino benzyloxycarbonyl (PABC)), thiosulfonate linker (via disulfide exchange), hydrazine-maleimide linker if the drug has a ketone or aldehyde function, iodoacetamides, MTS reagents (MethaneThioSulfonate).

[0756] Thus, in a preferred embodiment, the HSA-nanocamer system for drug delivery comprises:

[0757] A) a human serum albumin (HSA);

[0758] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0759] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA via a drug linker; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, and wherein the drug linker is functionalized with a thiol-reactive functional group reacting with free thiols on said HSA. Preferably, the HSA-nanocarrier system for drug delivery comprises:

[0760] A) a human serum albumin (HSA);

[0761] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0762] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA via a drug linker; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, and wherein the drug linker is functionalized with a thiol-reactive functional group reacting with free thiols on said HSA, wherein the thiol-reactive functional group is selected from pyridinyldithiol-ethoxy-carbonyl-group, maleimide, mc-vc-pabc linker (maleimidocaproyl (me) - valine-citrulline (vc)-para-amino benzyloxycarbonyl (PABC)), thiosulfonate linker, hydrazine-maleimide linker, iodoacetamides, and MTS reagents (MethaneThioSulfonate).

[0763] Particularly preferred thiol-reactive functional groups are pyridinyldithio, maleimide, and vinylsulfone groups. Thus, in a preferred embodiment, the HSA-nanocarrier system for drug delivery comprises:

[0764] A) a human serum albumin (HSA);

[0765] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0766] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA via a drug linker; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, and wherein the drug linker is functionalized with a pyridinyldithio group, maleimide group, or vinylsulfone group reacting with free thiols on said HSA.

[0767] Preferred pyridinyldithio-based linkers are pyridinyldithio ethyl carbonate, pyridinyldithio-propionyl-hydrazide (PDBH), pyridyldithio-ethylamine, pyridyldithio- NHS (e.g. SPDP: succinimidyl 3-(2-pyridyldithio)propionate, SPP: N-succinimidyl 4-(2-pyridyldithio)pentanoate, SPDB: N-Succinimidyl-3-(2-pyridyldithio)butyrate), pyridyldithio-PEGn-NHS, DMAC-SPDP (DMAC = (1-(4-((5-

[0768] (dimethylcarbamoyl)pyridin-2-yl)disulfanyl)butanoyloxy))), DMAC-SPP, pyridinyldithio-PEGn-carboxylic acid, PDB-PFP (perfluorophenyl 4-(pyridin-2- yldisulfaneyl)butanoate), PDEC-NB (2-methyl-2-(pyridin-2-yldisulfaneyl)propyl (4- nitrophenyl) carbonate), and PPC-NB (4-nitrophenyl 2-(pyridin-2-yldisulfanyl)propyl carbonate). Thus, in a preferred embodiment, the HSA-nanocarrier system for drug delivery comprises:

[0769] A) a human serum albumin (HSA);

[0770] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0771] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA via a drug linker; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, and wherein the drug linker is selected from pyridinyldithio ethyl carbonate, pyridinyldithio- propionyl-hydrazide, pyridyldithio-ethylamine, SPDP, SPP, SPDB, pyridyldithio- PEGn-NHS, DMAC-SPDP, DMAC-SPP, pyridinyldithio-PEGn-carboxylic acid, PDB-PFP, PDEC-NB, and PPC-NB.

[0772] Preferred maleimide-based linkers are maleim ide-carboxylic acids (e.g.3- maleimidopropionic acid), maleimide-amide-PEGn-va-PABC-PNP, maleimide- PEGn-vc-PABC-PNP, mc-vc-PABC-PNP, mc-Val-Cit-PAB-CI, mcc-vc-PAPC-PNP, mcc-PEGn-PABC, mc-va linker (me: maleimidocaproyl), mcc-va linker (mcc: maleimidomethyl cyclohexane-1 -carboxylate), mc-va-nhs linker, mcc-va-nhs linker, mc-Gly-Gly-Phe-Gly-PABC, and maleim ide-hydrazide. Thus, in a preferred embodiment, the HSA-nanocarrier system for drug delivery comprises:

[0773] A) a human serum albumin (HSA);

[0774] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0775] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA via a drug linker; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, and wherein the drug linker is selected from maleimide-carboxylic acid, maleimide-amide- PEGn-va-PABC-PNP, maleimide-PEGn-vc-PABC-PNP, mc-vc-PABC-PNP, mc- Val-Cit-PAB-CI, mcc-vc-PAPC-PNP, mcc-PEGn-PABC, mc-va linker, mcc-va linker, mc-va-nhs linker, mcc-va-nhs linker, mc-Gly-Gly-Phe-Gly-PABC, and maleimide-hydrazide.

[0776] In a preferred embodiment, the HSA-nanocarrier system for drug delivery comprises:

[0777] A) a human serum albumin (HSA); B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0778] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA via a cleavable drug linker; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, and wherein the cleavable drug linker is selected from pyridinyldithio ethyl carbonate, pyridinyldithio-propionyl-hydrazide, pyridyldithio-ethylamine, SPDP, SPP, SPDB, pyridyldithio-PEGn-NHS, DMAC-SPDP, DMAC-SPP, pyridinyldithio-PEGn- carboxylic acid, PDB-PFP, PDEC-NB, PPC-NB, maleim ide-carboxylic acid, maleimide-amide-PEGn-va-PABC-PNP, maleimide-PEGn-vc-PABC-PNP, mc-vc- PABC-PNP, mc-Val-Cit-PAB-CI, mcc-vc-PAPC-PNP, mcc-PEGn-PABC, mc-va linker, mcc-va linker, mc-va-nhs linker, mcc-va-nhs linker, mc-Gly-Gly-Phe-Gly- PABC, maleim ide-hydrazide, and vinylsulfone-carbonate.

[0779] In a preferred embodiment, the HSA-nanocamer system for drug delivery comprises:

[0780] A) a human serum albumin (HSA);

[0781] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0782] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA via a drug linker; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, and wherein the drug linker is selected from pyridinyldithio ethyl carbonate, pyridinyldithio- propionyl-hydrazide, pyridyldithio-ethylamine, SPDP, SPP, SPDB, pyridyldithio- PEGn-NHS, DMAC-SPDP, DMAC-SPP, pyridinyldithio-PEGn-carboxylic acid, PDB-PFP, PDEC-NB, PPC-NB, maleim ide-carboxylic acid, maleimide-amide- PEGn-va-PABC-PNP, maleimide-PEGn-vc-PABC-PNP, mc-vc-PABC-PNP, mc- Val-Cit-PAB-CI, mcc-vc-PAPC-PNP, mcc-PEGn-PABC, mc-va linker, mcc-va linker, mc-va-nhs linker, mcc-va-nhs linker, mc-Gly-Gly-Phe-Gly-PABC, maleim ide-hydrazide, vinylsulfone-carbonate, thiosulfonate linker, hydrazide- maleimide linker, iodoacetamide linker, and methanethiosulfonate linker.

[0783] The term "traceless drug linker" or “self-immolative drug linker” as used herein refers to a cleavable drug linker comprising a bifunctional chemical moiety, which is capable of covalently linking together the immunomodulatory drug with HSA in spaced manner into a normally stable nanocarrier system, but which becomes labile upon activation (e.g., nucleophilic attack, protease) leading to rapid cleavage of the moiety and release of the immunomodulatory drug from the mannosylated HSA in its active form. In other words, when the traceless drug linker is activated by a specific stimulus, it undergoes spontaneous intramolecular disassembling, in which it is broken down to its building blocks, and the immunomodulatory drug and mannosylated HSA are released, each without a remaining fragment of the linker.

[0784] Preferred “traceless drug linkers" are selected from the group consisting of pyridinyldithiol-ethoxy-carbonyl, and mc-vc-pabc linker.

[0785] The traceless PABC drug linker allows the release of the immunomodulatory drug containing at least one amine, phenol, carboxylic acid, or thiol functionality upon cleavage of the protease-cleavable substrate by endogenous or exogenous proteases and 1 ,6-spontaneous fragmentation. Cleavage kinetics is independent of the identity of released amine, phenol, carboxylic acid, or thiol molecules. Moreover, PABC can enhance the cleavage rate due to the presence of the p-aminobenzyl group.

[0786] Table 1 Summary of schematic symbols used herein and with the corresponding description and coding

[0787] Thus, the present invention is directed to an HSA-nanocamer system for drug delivery, wherein said nanocarrier system comprises: A) a human serum albumin (HSA);

[0788] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0789] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering.

[0790] Preferably, the HSA nanocarrier system has a diameter in the range comprised between 4 nm and 100 nm. More preferably, the HSA nanocarrier system has a diameter in the range comprised between 4 nm and 20 nm.

[0791] In all HSA-nanocarrier systems disclosed herein the use of trimannose moieties is preferred. Pharmaceutical compositions

[0792] “Pharmaceutical composition” refers to a preparation in a form that allows the biological activity of the active ingredient(s) to be effective, and which contain no additional components which are toxic to the subjects to which the formulation is administered.

[0793] As used herein, the terms "pharmaceutically acceptable", "physiologically tolerable" and grammatical variations thereof, are used interchangeably and represent that the materials are capable of administration to or upon a mammal without the production of undesirable physiological effects such as nausea, dizziness, gastric upset and the like.

[0794] The pharmaceutical composition is designed to facilitate the administering of the inventive HSA nanocarrier system in an effective manner.

[0795] “Pharmaceutically acceptable excipient” refers to an ingredient in a pharmaceutical formulation, other than an active ingredient, which is nontoxic to the subject to whom it is administered. A pharmaceutically acceptable excipient includes, but is not limited to, a buffer, stabilizer, or preservative.

[0796] Examples of suitable excipients include, without limitation, lactose, dextrose, sucrose, glucose, powdered sugar, sorbitol, mannitol, xylitol, starches, acacia gum, xanthan gum, guar gum, tara gum, mesquite gum, fenugreek gum, locust bean gum, ghatti gum, tragacanth gum, inositol, molasses, maltodextrin, extract of Irish moss, panwar gum, mucilage of isapol husks, Veegum, larch arabogalactan, calcium silicate, calcium phosphate, dicalcium phosphate, calcium sulfate, kaolin, sodium chloride, polyethylene glycol, alginates, gelatine, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, saline, syrup, methylcellulose, ethylcellulose, hydroxypropylnethylcellulose, carboxymethylcellulose, polyacrylic acids such as Carbopols, such as Carbopol941 , Carbopol980, Carbopol981 ,and gum bases such as Pharmagum™ (SPI Pharma Group; New Castle, Del.), and similar. Typically, the compositions of the present invention comprise from about 10% to about 90% by weight of the excipient or combinations thereof.

[0797] Preferably, the pharmaceutical composition contains from about 0.001 % to about 90%, preferably from about 0.01 % to about 75%, more preferably from about 0.1 % to 50%, and still more preferably from about 0.1 % to 10% by weight of the HSA nanocarrier system of the present invention, with the remainder consisting of suitable pharmaceutical excipients, and / or diluents.

[0798] The pharmaceutical composition can be formulated into powders, granules, tablets, capsules, suspensions, emulsions, syrups, oral dosage form, external preparation, suppository or in the form of sterile injectable solutions, such as aerosolized in a usual manner, respectively. When formulated, it can be prepared using a diluent or excipient such as generally used fillers, extenders, binders, wetting agents, disintegrating agents, surface active agents.

[0799] In the pharmaceutical composition, the solid preparation for oral administration may be a tablet, pill, powder, granule, or capsule. The solid preparation may further comprise an excipient. Excipients may be, for example, starch, calcium carbonate, sucrose, lactose, or gelatine. In addition, the solid preparation may further comprise a lubricant, such as magnesium stearate, or talc. In the pharmaceutical composition, liquid preparations for oral administration may be best suspensions, solutions, emulsions, or syrups. The liquid formulation may comprise water, or liquid paraffin. The liquid formulation may, for excipients, for example, include wetting agents, sweeteners, aromatics or preservatives. For the purposes of parenteral administration, compositions containing the HSA nanocamer system of the invention are preferably dissolved in distilled water and the pH preferably adjusted to about 6 to 8.

[0800] Useful preparations of the compositions of the invention for parenteral administration also include sterile aqueous and non-aqueous solvents, suspensions and emulsions. Examples of useful non-aqueous solvents include propylene glycol, polyethylene glycol, vegetable oil, fish oil, and injectable organic esters.

[0801] An embodiment of the present invention is directed to a pharmaceutical composition comprising an HSA nanocamer system for drug delivery into a target cell and a pharmaceutically acceptable excipient and / or diluent, wherein said nanocarrier system comprises:

[0802] A) a human serum albumin (HSA);

[0803] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0804] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering.

[0805] Preferably, the pharmaceutical composition comprises an HSA-nanocamer system for drug delivery and a pharmaceutically acceptable excipient and / or diluent, wherein the HSA nanocamer system comprises:

[0806] A) a human serum albumin (HSA);

[0807] B) a plurality of dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0808] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering.

[0809] Preferably, the pharmaceutical composition comprises an HSA-nanocamer system for drug delivery and a pharmaceutically acceptable excipient and / or diluent, wherein the HSA nanocamer system comprises:

[0810] A) a human serum albumin (HSA);

[0811] B) a plurality of monomannose moieties, dimannose moieties or trimannose moieties covalently bound to said HSA;

[0812] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering.

[0813] Preferably, the pharmaceutical composition comprises an HSA-nanocamer system for drug delivery and a pharmaceutically acceptable excipient and / or diluent, wherein the HSA nanocamer system comprises:

[0814] A) a human serum albumin (HSA);

[0815] B) a plurality of monomannose moieties, dimannose moieties or trimannose moieties covalently bound to said HSA;

[0816] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA the fluorescent dye is a fluorescent dye maleimide selected from the group consisting of sulfo-cyanin-maleimide, Alexa Fluor-maleimide, and cyanin- maleimide; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering. Preferably, the pharmaceutical composition comprising an HSA nanocamer system for drug delivery into a target cell and a pharmaceutically acceptable excipient and / or diluent, wherein said nanocamer system comprises:

[0817] A) a human serum albumin (HSA);

[0818] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0819] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, and wherein the HSA bound to the plurality of mannose moieties and to the at least one immunomodulatory drug is backfolded by a rapid dilution step.

[0820] Preferably, the pharmaceutical composition comprising an HSA nanocamer system for drug delivery into a target cell and a pharmaceutically acceptable excipient and / or diluent, wherein said nanocamer system comprises:

[0821] A) a human serum albumin (HSA);

[0822] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0823] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, and wherein the plurality of dimannose moieties or trimannose moieties is selected from the group consisting of ManpNs, ManpsNs, (Manp)3N3, and (Manp3)3N3, preferably ManpsNs.

[0824] Preferably, the pharmaceutical composition comprises an HSA-nanocamer system for drug delivery and a pharmaceutically acceptable excipient and / or diluent, wherein the HSA nanocamer system comprises:

[0825] A) a human serum albumin (HSA);

[0826] B) a plurality of monomannose moieties, dimannose moieties or trimannose moieties covalently bound to said HSA;

[0827] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, and wherein the immunomodulatory drug is covalently bound to said HSA via a cleavable drug linker comprising a thiol-reactive functional group selected from selected from pyridinyldithio-ethoxy-carbonyl-group, maleimide, mc-vc-pabc linker (maleimidocaproyl (me) - valine-citrulline (vc) -para-amino benzyloxycarbonyl (PABC)), thiosulfonate linker, hydrazide-maleimide linker, iodoacetamide linker, and methanethiosulfonate linker.

[0828] Preferably, the pharmaceutical composition comprises an HSA-nanocamer system for drug delivery and a pharmaceutically acceptable excipient and / or diluent, wherein the HSA nanocamer system comprises:

[0829] A) a human serum albumin (HSA);

[0830] B) a plurality of monomannose moieties, dimannose moieties or trimannose moieties covalently bound to said HSA;

[0831] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, and wherein the immunomodulatory drug is covalently bound to said HSA via a cleavable drug linker comprising a thiol-reactive functional group, wherein the linker is covalently bound to a ketone or aldehyde group of the immunomodulatory drug and the linker is selected from methanethiosulfonate, thiosulfonate, and maleimide-hydrazide (e.g. BMPH (N-[3-maleimidopropionic acid hydrazide)).

[0832] Preferably, the pharmaceutical composition comprises an HSA-nanocamer system for drug delivery and a pharmaceutically acceptable excipient and / or diluent, wherein the HSA nanocamer system comprises:

[0833] A) a human serum albumin (HSA);

[0834] B) a plurality of monomannose moieties, dimannose moieties or trimannose moieties covalently bound to said HSA;

[0835] C) at least one immunomodulatory drug selected from TLR7 / 8 agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering.

[0836] Preferably, the HSA-nanocamer system for drug delivery, comprises:

[0837] A) a human serum albumin (HSA);

[0838] B) a plurality of monomannose moieties, dimannose moieties or trimannose moieties covalently bound to said HSA; C) at least one immunomodulatory drug selected from TLR7 / 8 agonist or Cucurbitacin B covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering.

[0839] Preferably, the pharmaceutical composition comprises an HSA-nanocamer system for drug delivery and a pharmaceutically acceptable excipient and / or diluent, wherein the HSA nanocamer system comprises:

[0840] A) a human serum albumin (HSA);

[0841] B) a plurality of monomannose moieties, dimannose moieties or trimannose moieties covalently bound to said HSA;

[0842] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an interconnecting molecule comprising polyethylene glycol with a number of ethylene glycol repeating units between 2 and 10.

[0843] Preferably, the pharmaceutical composition comprises an HSA-nanocamer system for drug delivery and a pharmaceutically acceptable excipient and / or diluent, wherein the HSA nanocamer system comprises:

[0844] A) a human serum albumin (HSA);

[0845] B) a plurality of monomannose moieties, dimannose moieties or trimannose moieties covalently bound to said HSA;

[0846] C) at least one immunomodulatory drug selected from TLR7 / 8 agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an NHS-PEGn-DBCO interconnecting molecule.

[0847] Preferably, the pharmaceutical composition comprises an HSA-nanocamer system for drug delivery and a pharmaceutically acceptable excipient and / or diluent, wherein the HSA nanocamer system comprises:

[0848] A) a human serum albumin (HSA); B) a plurality of monomannose moieties, dimannose moieties or trimannose moieties covalently bound to said HSA;

[0849] C) at least one immunomodulatory drug selected from TLR7 / 8 agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an interconnecting molecule selected from NHS- DBCO, NHS-PEGn-DBCO, BCN-Endo-NHS, BCN-Endo-PEGn-NHS, NHS-DIBO, NHS-PEGn-DIBO, NHS-DIFO, NHS-PEGn-DIFO, NHS-BCN, NHS-PEGn-BCN, NHS-TCO, NHS-PEGn-TCO, NHS-alkyne, NHS-PEGn-alkyne, NHS-azide, NHS- PEGn-Azide, STP-DBCO, STP-PEGn-DBCO, BCN-Endo-STP, BCN-Endo-PEGn- STP, STP-DIBO, STP-PEGn-DIBO, STP-DIFO, STP-PEGn-DIFO, STP-BCN, STP-PEGn-BCN, STP-TCO, STP-PEGn-TCO, STP-alkyne, STP-PEGn-alkyne, STP-azide, STP-PEGn-Azide, TFP-DBCO, TFP-PEGn-DBCO, BCN-Endo-TFP, BCN-Endo-PEGn-TFP, TFP-DIBO, TFP-PEGn-DIBO, TFP-DIFO, TFP-PEGn- DIFO, TFP-BCN, TFP-PEGn-BCN, TFP-TCO, TFP-PEGn-TCO, TFP-alkyne, TFP- PEGn-alkyne, TFP-azide, TFP-PEGn-Azide, PTP-DBCO, PTP-PEGn-DBCO, BCN-Endo-PTP, BCN-Endo-PEGn-PTP, PTP-DIBO, PTP-PEGn-DIBO, PTP- DIFO, PTP-PEGn-DIFO, PTP-BCN, PTP-PEGn-BCN, PTP-TCO, PTP-PEGn- TCO, PTP-alkyne, PTP-PEGn-alkyne, PTP-azide, PTP-PEGn-Azide, NPC-DBCO, NPC-PEGn-DBCO, BCN-Endo-NPC, BCN-Endo-PEGn-NPC, NPC-DIBO, NPC- PEGn-DIBO, NPC-DIFO, NPC-PEGn-DIFO, NPC-BCN, NPC-PEGn-BCN, NPC- TCO, NPC-PEGn-TCO, NPC-alkyne, NPC-PEGn-alkyne, NPC-azide, NPC-PEGn- Azide, NCS-azide, NCS-PEGn-azide, NCS-alkyne, NCS-PEGn-alkyne, NCS- DBCO, NCS-PEGn-DBCO, BCN-Endo-NCS, BCN-Endo-PEGn-NCS, NCS-DIBO, NCS-PEGn-DIBO, NCS-DIFO, NCS-PEGn-DIFO, NCS-BCN, NCS-PEGn-BCN, DBCO-COOH, DBCO-PEGn-COOH, BCN-Endo-COOH, BCN-Endo-PEGn- COOH, BCN-COOH, BCN-PEGn-COOH, DIBO-COOH, DIBO-PEGn-COOH, DIFO-COOH, DIFO-PEGn-COOH, Alkyne-COOH, and Alkyne-PEGn-COOH, and wherein n represents the number of ethylene glycol repeating units between 2 and 10.

[0850] Preferably, the interconnecting molecule is selected from NHS-PEGn-DBCO, Endo-BCN-PEGn-NHS, NHS-PEGn-DIBO, NHS-PEGn-DIFO, NHS-PEGn-BCN, NHS-DBCO, Amine-PEGn-DBCO, Amine-DBCO, Acid-PEGn-DBCO, Acid-DBCO, STP-PEGn-DBCO, STP-DBCO, TFP-DBCO, TFP-PEGn-DBCO, PTP-PEGn- DBCO, and PTP-DBCO, wherein n represents the number of ethylene glycol repeating units between 2 and 10.

[0851] Preferably, the pharmaceutical composition comprises an HSA-nanocamer system for drug delivery and a pharmaceutically acceptable excipient and / or diluent, wherein the HSA nanocamer system comprises:

[0852] A) a human serum albumin (HSA);

[0853] B) a plurality of monomannose moieties, dimannose moieties or trimannose moieties covalently bound to said HSA;

[0854] C) at least one immunomodulatory drug selected from TLR7 / 8 agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, and wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an NHS-PEGn-DBCO interconnecting molecule, and the molar ratio of the interconnecting molecule to HSA is comprised between 3 and 59, and / or wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59.

[0855] Preferably, the pharmaceutical composition comprises an HSA-nanocamer system for drug delivery and a pharmaceutically acceptable excipient and / or diluent, wherein the HSA nanocamer system comprises:

[0856] A) a human serum albumin (HSA);

[0857] B) a plurality of monomannose moieties, dimannose moieties or trimannose moieties covalently bound to said HSA;

[0858] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, and wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an NHS-PEGn-DBCO interconnecting molecule, and the molar ratio of the interconnecting molecule to HSA is comprised between 3 and 59, and wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59.

[0859] Preferably, the pharmaceutical composition comprises an HSA-nanocamer system for drug delivery and a pharmaceutically acceptable excipient and / or diluent, wherein the HSA nanocamer system comprises: A) a human serum albumin (HSA);

[0860] B) a plurality of monomannose moieties, dimannose moieties or trimannose moieties covalently bound to said HSA;

[0861] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an NHS-PEGn-DBCO interconnecting molecule, and the molar ratio of the interconnecting molecule to HSA is comprised between 3 and 59, wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59, wherein the molar ratio of the immunomodulatory drug to HSA is comprised between 1 and 30, and wherein the plurality of dimannose moieties or trimannose moieties are selected from the group consisting of ManpNs, ManpsNs, (Manp)3N3, and (Manps^Ns, preferably ManpsNs.

[0862] Preferably, the pharmaceutical composition comprises an HSA-nanocamer system for drug delivery and a pharmaceutically acceptable excipient and / or diluent, wherein the HSA nanocamer system comprises:

[0863] A) a human serum albumin (HSA);

[0864] B) a plurality of monomannose moieties, dimannose moieties or trimannose moieties covalently bound to said HSA;

[0865] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an interconnecting molecule comprising polyethylene glycol with a number of ethylene glycol repeating units between 2 and 10, and the molar ratio of the interconnecting molecule to HSA is comprised between 3 and 59, wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59, wherein the molar ratio of the immunomodulatory drug to HSA is comprised between 1 and 30, and wherein the plurality of dimannose moieties or trimannose moieties are selected from the group consisting of ManpsNs, and (Manp3)3N3, preferably ManpsNs, and wherein the HSA bound to the plurality of mannose moieties and to the at least one immunomodulatory drug is backfolded by a rapid dilution step. Preferably, the pharmaceutical composition comprises an HSA-nanocamer system for drug delivery and a pharmaceutically acceptable excipient and / or diluent, wherein the HSA nanocamer system comprises:

[0866] A) a human serum albumin (HSA);

[0867] B) a plurality of monomannose moieties, dimannose moieties or trimannose moieties covalently bound to said HSA;

[0868] C) at least one immunomodulatory drug selected from TLR agonist or Cucurbitacin B covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an NHS-PEGn-DBCO interconnecting molecule, and the molar ratio of the interconnecting molecule to HSA is comprised between 3 and 59, wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59, wherein the molar ratio of the immunomodulatory drug to HSA is comprised between 1 and 30, and wherein the plurality of dimannose moieties or trimannose moieties is selected from the group consisting of ManpNs, ManpsNs, (Manp)3N3, and (Manps^Ns, preferably ManpsNs, and wherein the HSA bound to the plurality of mannose moieties and to the at least one immunomodulatory drug is backfolded by a rapid dilution step, and wherein the immunomodulatory drug is covalently bound to said HSA via a cleavable drug linker comprising a thiol-reactive functional group selected from pyridinyldithio- ethoxy-carbonyl-group, maleimide, mc-vc-pabc linker (maleimidocaproyl (me) - valine-citrulline (vc) -para-amino benzyloxycarbonyl (PABC)), thiosulfonate linker, hydrazide-maleimide linker, iodoacetamide linker, and methanethiosulfonate linker.

[0869] Preferably, the pharmaceutical composition comprises an HSA-nanocamer system for drug delivery and a pharmaceutically acceptable excipient and / or diluent, wherein the HSA nanocamer system comprises:

[0870] A) a human serum albumin (HSA);

[0871] B) a plurality monomannose moieties, dimannose moieties or trimannose moieties covalently bound to said HSA;

[0872] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties is covalently bound to the HSA via an NHS-PEGn-DBCO interconnecting molecule, and the molar ratio of the interconnecting molecule to HSA is comprised between 3 and 59, wherein the molar ratio of the plurality of mannose moieties to HSA is comprised between 1 and 59, wherein the molar ratio of the immunomodulatory drug to HSA is comprised between 1 and 30, and wherein the plurality of dimannose moieties or trimannose moieties are selected from the group consisting of ManpsNs, and (Manp3)3N3, preferably ManpsNs, and wherein the HSA bound to the plurality of mannose moieties and to the at least one immunomodulatory drug is backfolded by a rapid dilution step, and wherein the immunomodulatory drug is covalently bound to said HSA via a cleavable drug linker comprising a thiolreactive functional group, wherein the linker is covalently bound to a ketone or aldehyde group of the immunomodulatory drug and the linker is selected from methanethiosulfonate, thiosulfonate, and maleimide-hydrazide (e.g. BMPH (N-|3- maleimidopropionic acid hydrazide)).

[0873] Another preferred embodiment of the present invention is directed to a pharmaceutical composition comprising an HSA nanocarrier system for drug delivery and a pharmaceutically acceptable excipient and / or diluent, wherein the HSA nanocarrier system comprises:

[0874] A) a human serum albumin (HSA);

[0875] B) a plurality of monomannose moieties, dimannose moieties or trimannose moieties covalently bound to said HSA;

[0876] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA;

[0877] D) a fluorescent dye covalently bound to said HSA, wherein the fluorescent dye comprises a maleimide as thiol-reactive functional group or an NHS- ester as amine-reactive functional group, and wherein the fluorescent dye emits light in a range of 400 nm to 850 nm. wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering.

[0878] Another preferred embodiment of the present invention is directed to a pharmaceutical composition comprising an HSA nanocarrier system for drug delivery and a pharmaceutically acceptable excipient and / or diluent, wherein the HSA nanocarrier system comprises:

[0879] A) a human serum albumin (HSA);

[0880] B) a plurality of monomannose moieties, dimannose moieties or trimannose moieties covalently bound to said HSA; C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA;

[0881] D) a fluorescent dye covalently bound to said HSA, wherein the fluorescent dye comprises a maleimide as thiol-reactive functional group, and wherein the fluorescent dye emits light in a range of 400 nm to 850 nm. wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, and wherein the fluorescent dye is selected from the group consisting of sulfo-cyanin- maleimide, Alexa Fluor-maleimide, and cyanin-maleimide.

[0882] Another embodiment of the present invention is directed to a pharmaceutical composition comprising an HSA nanocamer system for drug delivery into a target liver cell expressing a mannose surface receptor and a pharmaceutically acceptable excipient and / or diluent, wherein the HSA nanocarrier system comprises:

[0883] A) a human serum albumin (HSA);

[0884] B) a plurality of monomannose moieties, dimannose moieties or trimannose moieties covalently bound to said HSA;

[0885] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering.

[0886] Another embodiment of the present invention is directed to a pharmaceutical composition comprising an HSA nanocamer system for drug delivery into a target liver cell expressing a mannose surface receptor and a pharmaceutically acceptable excipient and / or diluent, wherein the HSA nanocarrier system comprises:

[0887] A) a human serum albumin (HSA);

[0888] B) a plurality of monomannose moieties, dimannose moieties or trimannose moieties covalently bound to said HSA;

[0889] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, and wherein the target liver cells express a mannose surface receptor selected from the group consisting of CD206, CD209, and homologues thereof. Another embodiment of the present invention is directed to a pharmaceutical composition comprising an HSA nanocamer system for drug delivery into a target liver cell expressing a mannose surface receptor and a pharmaceutically acceptable excipient and / or diluent, wherein the HSA nanocarrier system comprises:

[0890] A) a human serum albumin (HSA);

[0891] B) a plurality of monomannose moieties, dimannose moieties or trimannose moieties covalently bound to said HSA;

[0892] C) at least one immunomodulatory drug selected from TLR agonist or STAT3 inhibitor covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, and wherein the target cells are selected from the group consisting of dendritic cells, macrophages, B cells, T cells, liver non-parenchymal cells, splenic cells, neutrophils, and cultured cells expressing an exogenous surface mannose receptor.

[0893] Another preferred embodiment of the present invention is directed to a pharmaceutical composition comprising an HSA nanocarrier system for drug delivery into a target liver cell expressing a mannose surface receptor and a pharmaceutically acceptable excipient and / or diluent, wherein the HSA nanocarrier system comprises: trimannose bound via a NHS-PEGn-DBCO interconnecting molecule to HSA at a molar trimannose: HSA range comprised between 1 and 59;

[0894] Cucurbitacin B or TLR7 / 8 agonist as an immunomodulatory drug at a molar drug: HSA range preferably comprised between 5 and 27, wherein the immunomodulatory drug is covalently bound to said HSA by a cleavable drug linker; optionally a sulfo-Cyanin5-maleimide dye or a sulfo-Cyanin7.5-maleimide dye conjugated to said HSA and wherein said HSA nanocamer system has a diameter in the range comprised between 4 nm and 150 nm.

[0895] Preparation of HSA-nanocarrier systems Another aspect of the present invention is directed to a method to manufacture a HSA nanocarrier system as described herein, wherein the method comprises the following steps: i.) providing monomolecular native HSA, wherein the monomolecular native

[0896] HSA is optionally labeled with a fluorescent dye; ii.) attaching an interconnecting molecule to the HSA; iii.) covalently binding of a plurality of monomannose or dimannose or trimannose moieties to the interconnecting molecule to obtain mannosylated HSA; iv.) denaturing of the mannosylated HSA obtained at step iii.; v.-a) covalently binding of at least one immunomodulatory drug to said denatured mannosylated HSA, wherein the one or more immunomodulatory drugs are attached to a cleavable drug linker comprising a thiol-reactive functional group; v.-b) capping of unreacted thiols, preferably with N-ethylmaleimide; v.-c) washing the denatured nanocarrier system obtained in step v.-b; vi.) backfolding of the denatured nanocarrier system via rapid dilution procedure; vii.) obtaining a monomolecular HSA nanocamer system, wherein the HSA nanocamer system comprises:

[0897] A) a human serum albumin (HSA);

[0898] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0899] C) at least one immunomodulatory drug covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering.

[0900] In step iv. of the method to manufacture the inventive HSA-nanocamer system, denaturing of the mannosylated HSA results in the release of thiol groups by reduction of native disulfides to which in the later steps the immunomodulatory drug is covalently bound. Preferably, the mannosylated HSA is completely denatured in step iv.

[0901] In step v.-a of the method to manufacture the inventive HSA-nanocarrier system, the at least one immunomodulatory drug is preferably covalently bound to the mannosylated HSA via a disulfide exchange reaction. The free thiols of HSA resulting from the denaturation step react with a thiol-reactive functional group (such as pyridinyldithio-ethoxy-carbonyl-group or maleimide) attached to the at least one immunomodulatory drug.

[0902] In step vi. of the method to manufacture the inventive HSA-nanocamer system, the backfolding is preferably carried out such that not the exact native conformation of HSA is obtained, but an a-helix-based globular structure of the monomolecular HSA nanocarrier system

[0903] In one embodiment, the inventive HSA-nanocamer system comprises at least two immunomodulatory drugs. Thus, the method to manufacture a HSA nanocamer system as described herein, comprises the following steps: i.) providing monomolecular native HSA, wherein the monomolecular native

[0904] HSA is optionally labeled with a fluorescent dye; ii.) attaching an interconnecting molecule to the HSA; iii.) covalently binding of a plurality of monomannose or dimannose or trimannose moieties to the interconnecting molecule to obtain mannosylated HSA; iv.) denaturing of the mannosylated HSA obtained at step iii.; v.-a1 ) covalently binding of an immunomodulatory drug to said denatured mannosylated HSA, wherein the one or more immunomodulatory drugs are attached to a cleavable drug linker comprising a thiol-reactive functional group, wherein the at least one immunomodulatory drug is not doxorubicin; v.-a2) repeating step v.-a1 with another immunomodulatory drug selected from TLR agonist or STAT3 inhibitor, until all immunomodulatory drugs are covalently bound to the denatured mannosylated HSA; v.-b) capping of unreacted thiols, preferably with N-ethylmaleimide; v.-c) washing the denatured nanocarrier system obtained in step v.-b; vi.) backfolding of the denatured nanocarrier system via rapid dilution procedure; vii.) obtaining a monomolecular HSA nanocamer system, wherein the HSA nanocamer system comprises:

[0905] A) a human serum albumin (HSA);

[0906] B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;

[0907] C) at least two immunomodulatory drugs r covalently bound to said HSA , wherein the at least two immunomodulatory drugs are not doxorubicin; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering. In a preferred embodiment of method to manufacture a HSA nanocarrier system as described herein, the method comprises the following steps: i.) providing monomolecular native HSA, wherein the monomolecular native

[0908] HSA is optionally labeled with a fluorescent dye; ii.) attaching an interconnecting molecule to the HSA; iii.) covalently binding of a plurality of monomannose or dimannose or trimannose moieties to the interconnecting molecule to obtain mannosylated HSA; iv.) denaturing of the mannosylated HSA obtained at step iii.; v.-a) covalently binding of at least one immunomodulatory drug to said denatured mannosylated HSA, wherein the one or more immunomodulatory drugs are attached to a cleavable drug linker comprising a thiol-reactive functional group, wherein the at least one immunomodulatory drug is not doxorubicin; v.-b) capping of unreacted thiols, preferably with N-ethylmaleimide; v.-c) washing the denatured nanocarrier system obtained in step v.-b; vi.) backfolding of the denatured nanocarrier system via rapid dilution procedure; vii.) obtaining a monomolecular HSA nanocamer system wherein the plurality of monomannose or dimannose or trimannose moieties is covalently bound to said HSA via an interconnecting molecule comprising polyethylene glycol with a number of ethylene glycol repeating units between 2 and 10.

[0909] In a preferred embodiment of method to manufacture a HSA nanocarrier system as described herein, the method comprises the following steps: i.) providing monomolecular native HSA, wherein the monomolecular native

[0910] HSA is optionally labeled with a fluorescent dye; ii.) attaching an interconnecting molecule to the HSA; iii.) covalently binding of a plurality of monomannose or dimannose or trimannose moieties to the interconnecting molecule to obtain mannosylated HSA; iv.) denaturing of the mannosylated HSA obtained at step iii.; v.-a) covalently binding of at least one immunomodulatory drug to said denatured mannosylated HSA, wherein the one or more immunomodulatory drugs are attached to a cleavable drug linker comprising a thiol-reactive functional group, wherein the at least one immunomodulatory drug is not doxorubicin; v.-b) capping of unreacted thiols, preferably with N-ethylmaleimide; v.-c) washing the denatured nanocarrier system obtained in step v.-b; vi.) backfolding of the denatured nanocarrier system via rapid dilution procedure; vii.) obtaining a monomolecular HSA nanocamer system wherein the plurality of monomannose or dimannose or trimannose moieties is covalently bound to said HSA via an interconnecting molecule selected from NHS- DBCO, NHS-PEGn-DBCO, BCN-Endo-NHS, BCN-Endo-PEGn-NHS, NHS-DIBO, NHS-PEGn-DIBO, NHS-DIFO, NHS-PEGn-DIFO, NHS-BCN, NHS-PEGn-BCN, NHS-TCO, NHS-PEGn-TCO, NHS-alkyne, NHS-PEGn-alkyne, NHS-azide, NHS- PEGn-Azide, STP-DBCO, STP-PEGn-DBCO, BCN-Endo-STP, BCN-Endo-PEGn- STP, STP-DIBO, STP-PEGn-DIBO, STP-DIFO, STP-PEGn-DIFO, STP-BCN, STP-PEGn-BCN, STP-TCO, STP-PEGn-TCO, STP-alkyne, STP-PEGn-alkyne, STP-azide, STP-PEGn-Azide, TFP-DBCO, TFP-PEGn-DBCO, BCN-Endo-TFP, BCN-Endo-PEGn-TFP, TFP-DIBO, TFP-PEGn-DIBO, TFP-DIFO, TFP-PEGn- DIFO, TFP-BCN, TFP-PEGn-BCN, TFP-TCO, TFP-PEGn-TCO, TFP-alkyne, TFP- PEGn-alkyne, TFP-azide, TFP-PEGn-Azide, PTP-DBCO, PTP-PEGn-DBCO, BCN-Endo-PTP, BCN-Endo-PEGn-PTP, PTP-DIBO, PTP-PEGn-DIBO, PTP- DIFO, PTP-PEGn-DIFO, PTP-BCN, PTP-PEGn-BCN, PTP-TCO, PTP-PEGn- TCO, PTP-alkyne, PTP-PEGn-alkyne, PTP-azide, PTP-PEGn-Azide, NPC-DBCO, NPC-PEGn-DBCO, BCN-Endo-NPC, BCN-Endo-PEGn-NPC, NPC-DIBO, NPC- PEGn-DIBO, NPC-DIFO, NPC-PEGn-DIFO, NPC-BCN, NPC-PEGn-BCN, NPC- TCO, NPC-PEGn-TCO, NPC-alkyne, NPC-PEGn-alkyne, NPC-azide, NPC-PEGn- Azide, NCS-azide, NCS-PEGn-azide, NCS-alkyne, NCS-PEGn-alkyne, NCS- DBCO, NCS-PEGn-DBCO, BCN-Endo-NCS, BCN-Endo-PEGn-NCS, NCS-DIBO, NCS-PEGn-DIBO, NCS-DIFO, NCS-PEGn-DIFO, NCS-BCN, NCS-PEGn-BCN, DBCO-COOH, DBCO-PEGn-COOH, BCN-Endo-COOH, BCN-Endo-PEGn- COOH, BCN-COOH, BCN-PEGn-COOH, DIBO-COOH, DIBO-PEGn-COOH, DIFO-COOH, DIFO-PEGn-COOH, Alkyne-COOH, and Alkyne-PEGn-COOH, wherein n represents the number of ethylene glycol repeating units between 2 and 10.

[0911] Preferably, the interconnecting molecule is selected from NHS-PEGn-DBCO, Endo-BCN-PEGn-NHS, NHS-PEGn-DIBO, NHS-PEGn-DIFO, NHS-PEGn-BCN, NHS-DBCO, Amine-PEGn-DBCO, Amine-DBCO, Acid-PEGn-DBCO, Acid-DBCO, STP-PEGn-DBCO, STP-DBCO, TFP-DBCO, TFP-PEGn-DBCO, PTP-PEGn- DBCO, and PTP-DBCO, wherein n represents the number of ethylene glycol repeating units between 2 and 10. In a preferred embodiment of method to manufacture a HSA nanocarrier system as described herein, the method comprises the following steps: i.) providing monomolecular native HSA, wherein the monomolecular native

[0912] HSA is optionally labeled with a fluorescent dye; ii.) attaching an interconnecting molecule to the HSA; iii.) covalently binding of a plurality of monomannose or dimannose or trimannose moieties to the interconnecting molecule to obtain mannosylated HSA; iv.) denaturing of the mannosylated HSA obtained at step iii.; v.-a) covalently binding of at least one immunomodulatory drug inhibitor to said denatured mannosylated HSA, wherein the one or more immunomodulatory drugs are attached to a cleavable drug linker comprising a thiol-reactive functional group, wherein the at least one immunomodulatory drug is not doxorubicin; v.-b) capping of unreacted thiols, preferably with N-ethylmaleimide; v.-c) washing the denatured nanocarrier system obtained in step v.-b; vi.) backfolding of the denatured nanocarrier system via rapid dilution procedure; vii.) obtaining a monomolecular HSA nanocamer system wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties are selected from the group consisting of ManpNs, ManpsNs, (Manp)3N3, and (Manp3)3N3, preferably ManpsNs.

[0913] In a preferred embodiment of method to manufacture a HSA nanocarrier system as described herein, the method comprises the following steps: i.) providing monomolecular native HSA, wherein the monomolecular native

[0914] HSA is optionally labeled with a fluorescent dye; ii.) attaching an interconnecting molecule to the HSA; iii.) covalently binding of a plurality of monomannose or dimannose or trimannose moieties to the interconnecting molecule to obtain mannosylated HSA; iv.) denaturing of the mannosylated HSA obtained at step iii.; v.-a) covalently binding of at least one immunomodulatory drug to said denatured mannosylated HSA, wherein the one or more immunomodulatory drugs are attached to a cleavable drug linker comprising a thiol-reactive functional group, wherein the at least one immunomodulatory drug is not doxorubicin; v.-b) capping of unreacted thiols, preferably with N-ethylmaleimide; v.-c) washing the denatured nanocarrier system obtained in step v.-b; vi.) backfolding of the denatured nanocarrier system via rapid dilution procedure; vii.) obtaining a monomolecular HSA nanocarrier system wherein the molar immunomodulatory drug: HSA ratio is comprised between 1 and 30.

[0915] In a preferred embodiment of method to manufacture a HSA nanocarrier system as described herein, the method comprises the following steps: i.) providing monomolecular native HSA, wherein the monomolecular native

[0916] HSA is optionally labeled with a fluorescent dye; ii.) attaching an interconnecting molecule to the HSA; iii.) covalently binding of a plurality of monomannose or dimannose or trimannose moieties to the interconnecting molecule to obtain mannosylated HSA; iv.) denaturing of the mannosylated HSA obtained at step iii.; v.-a) covalently binding of at least one immunomodulatory drug to said denatured mannosylated HSA, wherein the one or more i...

Claims

Claims1. An HSA-nanocarrier system for drug delivery, wherein said nanocarrier system comprises:A) a human serum albumin (HSA);B) a plurality of monomannose moieties, dimannose moieties, or trimannose moieties covalently bound to said HSA;C) at least one immunomodulatory drug covalently bound to said HSA; wherein said HSA nanocarrier system has a diameter in the range comprised between 4 nm and 150 nm, as measured by dynamic light scattering, wherein the at least one immunomodulatory drug is not doxorubicin.

2. The HSA-nanocarrier system according to claim 1 , wherein the plurality of monomannose or dimannose or trimannose moieties is covalently bound to said HSA via an interconnecting molecule comprising polyethylene glycol with a number of ethylene glycol repeating units between 2 and 10.

3. The HSA-nanocarrier system according to claim 1 or 2, wherein the plurality of monomannose or dimannose or trimannose moieties is covalently bound to said HSA via an interconnecting molecule selected from NHS-DBCO, NHS-PEGn-DBCO, BCN-Endo-NHS, BCN-Endo-PEGn-NHS, NHS-DIBO, NHS-PEGn-DIBO, NHS-DIFO, NHS-PEGn-DIFO, NHS-BCN, NHS-PEGn- BCN, NHS-TCO, NHS-PEGn-TCO, NHS-alkyne, NHS-PEGn-alkyne, NHS- azide, NHS-PEGn-Azide, STP-DBCO, STP-PEGn-DBCO, BCN-Endo-STP, BCN-Endo-PEGn-STP, STP-DIBO, STP-PEGn-DIBO, STP-DIFO, STP- PEGn-DIFO, STP-BCN, STP-PEGn-BCN, STP-TCO, STP-PEGn-TCO, STP-alkyne, STP-PEGn-alkyne, STP-azide, STP-PEGn-Azide, TFP-DBCO, TFP-PEGn-DBCO, BCN-Endo-TFP, BCN-Endo-PEGn-TFP, TFP-DIBO, TFP-PEGn-DIBO, TFP-DIFO, TFP-PEGn-DIFO, TFP-BCN, TFP-PEGn- BCN, TFP-TCO, TFP-PEGn-TCO, TFP-alkyne, TFP-PEGn-alkyne, TFP- azide, TFP-PEGn-Azide, PTP-DBCO, PTP-PEGn-DBCO, BCN-Endo-PTP, BCN-Endo-PEGn-PTP, PTP-DIBO, PTP-PEGn-DIBO, PTP-DIFO, PTP- PEGn-DIFO, PTP-BCN, PTP-PEGn-BCN, PTP-TCO, PTP-PEGn-TCO, PTP-alkyne, PTP-PEGn-alkyne, PTP-azide, PTP-PEGn-Azide, NPC- DBCO, NPC-PEGn-DBCO, BCN-Endo-NPC, BCN-Endo-PEGn-NPC, NPC- DIBO, NPC-PEGn-DIBO, NPC-DIFO, NPC-PEGn-DIFO, NPC-BCN, NPC-PEGn-BCN, NPC-TCO, NPC-PEGn-TCO, NPC-alkyne, NPC-PEGn-alkyne, NPC-azide, NPC-PEGn-Azide, NCS-azide, NCS-PEGn-azide, NCS-alkyne, NCS-PEGn-alkyne, NCS-DBCO, NCS-PEGn-DBCO, BCN-Endo-NCS, BCN-Endo-PEGn-NCS, NCS-DIBO, NCS-PEGn-DIBO, NCS-DIFO, NCS- PEGn-DIFO, NCS-BCN, NCS-PEGn-BCN, DBCO-COOH, DBCO-PEGn- COOH, BCN-Endo-COOH, BCN-Endo-PEGn-COOH, BCN-COOH, BCN- PEGn-COOH, DIBO-COOH, DIBO-PEGn-COOH, DIFO-COOH, DIFO- PEGn-COOH, Alkyne-COOH, an Alkyne-PEGn-COOH, wherein n represents the number of ethylene glycol repeating units between 2 and 10.

4. The HSA-nanocarrier system according to any one of claims 1 - 3, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties are selected from the group consisting of ManpNs, ManpsNs, (Manp)3N3, and (Manps^Ns, preferably ManpsNs.

5. The HSA-nanocarrier system according to any one of claims 1 - 4, wherein the at least one immunomodulatory drug is covalently bound to said HSA via a drug linker selected from pyridinyldithio ethyl carbonate, pyridinyldithio-propionyl-hydrazide, pyridyldithio-ethylamine, SPDP, SPP, SPDB, pyridyldithio-PEGn-NHS, DMAC-SPDP, DMAC-SPP, pyridinyldithio- PEGn-carboxylic acid, PDB-PFP, PDEC-NB, PPC-NB, maleimide- carboxylic acid, maleimide-amide-PEGn-va-PABC-PNP, maleimide-PEGn- vc-PABC-PNP, mc-vc-PABC-PNP, mc-Val-Cit-PAB-CI, mcc-vc-PAPC-PNP, mcc-PEGn-PABC, mc-va linker, mcc-va linker, mc-va-nhs linker, mcc-va- nhs linker, mc-Gly-Gly-Phe-Gly-PABC, maleimide-hydrazide, vinylsulfone- carbonate, thiosulfonate linker, hydrazide-maleimide linker, iodoacetamide linker, and methanethiosulfonate linker.

6. The HSA nanocarrier system according to any one of claims 1 - 5, wherein the molar ratio of the plurality of monomannose or dimannose or trimannose moieties to HSA is comprised between 1 and 59.

7. The HSA nanocarrier system according to any one of claims 1 - 6, wherein the HSA-nanocarrier system further comprises:D) a fluorescent dye covalently bound to said HSA, wherein the fluorescent dye comprises a maleimide as thiol-reactive functional group or an NHS-ester as amine-reactive functional group, andwherein the fluorescent dye emits light in a range of 400 nm to 850 nm; and the fluorescent dye is a fluorescent dye maleimide selected from the group consisting of sulfo-cyanin-maleimide, Alexa Fluor-maleimide, and cyanin- maleimide.

8. The HSA nanocarrier system according to any one of claims 1 - 7, wherein the at least one immunomodulatory drug is selected from a TLR agonist or a STAT3 inhibitor.

9. The HSA nanocarrier system according to any one of claims 1 - 7, wherein the at least one immunomodulatory drug is selected from a TLR7 / 8 agonist or a STAT3 inhibitor.

10. The HSA nanocarrier system according to any one of claims 1 - 9, wherein said HSA nanocarrier system comprises: trimannose bound via an NHS-PEGn-DBCO interconnecting molecule to HSA at a molar trimannose: HSA range comprised between 1 and 59; Cucurbitacin B or a TLR7 / 8 agonist as an immunomodulatory drug at a molar drug: HSA range preferably comprised between 5 and 27, wherein the immunomodulatory drug is covalently bound to said HSA by a traceless, self-immolative pyridinyldithio-ethoxy-carbonyl drug linker; optionally a sulfo-Cyanin5-maleimide dye or a sulfo-Cyanin7.5- maleimide dye conjugated to said HSA.

11. The HSA nanocarrier system according to any one of claims 1 - 10, wherein the HSA is denatured.

12. A pharmaceutical composition comprising the HSA nanocarrier system according to any one of claims 1 - 11 and a pharmaceutical acceptable excipient.

13. A method to manufacture a HSA nanocarrier system according to any one of claims 1 - 12, wherein the method comprises the following steps: i.) providing monomolecular native HSA, wherein the monomolecular native HSA is optionally labeled with a fluorescent dye; ii.) attaching an interconnecting molecule to the HSA;iii.) covalently binding of a plurality of monomannose or dimannose or trimannose moieties to the interconnecting molecule to obtain mannosylated HSA; iv.) denaturing of the mannosylated HSA obtained at step iii.; v.-a) covalently binding of at least one immunomodulatory drug to said denatured mannosylated HSA, wherein the one or more immunomodulatory drugs are attached to a drug linker comprising a thiol-reactive functional group; v.-b) capping of unreacted thiols, preferably with N-ethylmaleimide; v.-c) washing the denatured nanocarrier system obtained in step v.-b; vi.) backfolding of the denatured nanocamer system via rapid dilution procedure; vii.) obtaining a monomolecular HSA nanocamer system, wherein the at least one immunomodulatory drug is not doxorubicin.

14. The method to manufacture a HSA nanocamer system according to claim 13 wherein the at least one immunomodulatory drug is selected from a TLR agonist or a STAT3 inhibitor.

15. The method to manufacture a HSA nanocamer system according to claim 13 or 14, wherein the plurality of monomannose or dimannose or trimannose moieties is covalently bound to said HSA via an interconnecting molecule comprising polyethylene glycol with a number of ethylene glycol repeating units between 2 and 10.

16. The method to manufacture a HSA nanocamer system according to any one of claims 13 - 15, wherein the plurality of monomannose moieties, dimannose moieties, or trimannose moieties are selected from the group consisting of ManpNs, ManpsNs, (Manp)3N3, and (Manp3)3N3, preferably ManpsNs.

17. The method to manufacture a HSA nanocamer system according to any one of claims 13 - 16, wherein the at least one immunomodulatory drug is covalently bound to said HSA by a drug linker selected from pyridinyldithio ethyl carbonate, pyridinyldithio-propionyl-hydrazide, pyridyldithioethylamine, SPDP, SPP, SPDB, pyridyldithio-PEGn-NHS, DMAC-SPDP, DMAC-SPP, pyridinyldithio-PEGn-carboxylic acid, PDB-PFP, PDEC-NB, PPC-NB, maleimide-carboxylic acid, maleimide-amide-PEGn-va-PABC-PNP, maleimide-PEGn-vc-PABC-PNP, mc-vc-PABC-PNP, mc-Val-Cit-PAB- Cl, mcc-vc-PAPC-PNP, mcc-PEGn-PABC, mc-va linker, mcc-va linker, mc- va-nhs linker, mcc-va-nhs linker, mc-Gly-Gly-Phe-Gly-PABC, maleimide- hydrazide, vinylsulfone-carbonate, thiosulfonate linker, hydrazide-maleimide linker, iodoacetamide linker, and methanethiosulfonate linker.

18. The method to manufacture a HSA nanocamer system according to claim any one of claims 13 - 17, wherein the HSA is labeled with a fluorescent dye emitting fluorescence in a range comprised between 400 and 850 nm via a maleimide and the method further comprises the following step i.1) before step ii.): i.1) subjecting the HSA labeled with a fluorescent dye maleimide to a ringopening hydrolysis by adding a buffer at a pH above 9.

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