Anti-microbial compositions and uses

Abstract

Provided herein are various compositions, such as nasal pharmaceutical compositions, which may be used for antiviral and / or antimicrobial therapies and / or prophylaxis.

Description

VAZO-701-WO-PCTOlANTI-MICROBIAL COMPOSITIONS AND USESCROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 749,338 filed January’ 24, 2025, which is incorporated herein by reference in its entirety’.BACKGROUND

[0002] The increasing virulence of both viruses and microbials has led to serous word outbreaks of viral epidemics historically, as well as equally dangerous microbials, where bacterial resistance is at almost untreatable levels. Various formulations offer antiviral and / or antimicrobial treatment and prophylaxis.SUMMARY

[0003] In some embodiments, provided herein are particles (e.g., nanoparticles) and compositions comprising such as particles (e.g., nanoparticles). In some embodiments, particles (e.g., nanoparticles) provided herein comprise a continuous matrix, liposome(s), micelle(s), or a combination thereof. In some embodiments, particles (e.g., nanoparticles (NP)) provided herein comprise a substrate system (e.g., forming liposomes or micelles). In some embodiments, particles (e.g., nanoparticles) provided herein comprise a substrate system. In specific embodiments, particles (e.g., nanoparticles) provided herein comprise a substrate system selected from the group consisting of (a) pH-sensitive liposomes, (b) glycyrrhizic acid nanoparticles (GANP), (c) epigallocatechin gallate (EGCG) nanoparticles, (d) mesoporous silica-coated metal nanoparticles (e.g., MSPAg-NP), and (e) micelles (e.g., comprising amphiphilic block copolymer, such as PEtOz-PLA).

[0004] In some embodiments, the composition comprises 1) a transition metal nanoparticle most preferably silver coated in mesoporous silica (e.g.. 0.1-100 ug / ml); 2) PEtOz-PLA deblock copolymer (pH sensitive micelles containing quercetin); 3) glycyrrhizic acid NP, (e.g., 0.1 -0.8 mg / ml, 40- 300 nM); 4) pH sensitive liposome, containing pH release (e.g., 10-15 nm) Ag NP intended silver incorporation into aqueous interior; and quercetin: PQQ or other in the liposomal lipid layer as well; 5) EGCG NP and Ag NP (e.g., about 20 nm on average), or any combination thereof.

[0005] In some embodiments, particles (e.g., nanoparticles) provided herein comprise a transitional metal (e.g., silver). In some embodiments, particles (e.g., nanoparticles) provided herein comprise a transitional metal (e.g., silver) coated with a mesoporous material (e.g., silica or silicon). In specific embodiments, particles (e.g., nanoparticles) provided herein comprise a transitional metal (e.g., silver) coated with mesoporous silica.VAZO-701-WO-PCTOl

[0006] In some embodiments, a composition provided herein comprises a mucoadhesive. In specific embodiments, particles (e.g., nanoparticles) provided herein comprise a mucoadhesive.

[0007] In some embodiments, a composition provided herein comprises an antioxidant. In specific embodiments, particles (e.g., nanoparticles) provided herein comprise an antioxidant.

[0008] In some embodiments, a composition provided herein comprises quercetin. In specific embodiments, particles (e.g., nanoparticles) provided herein comprise quercetin.

[0009] In some embodiments, a composition provided herein comprises glycyrrhizic acid. In specific embodiments, particles (e.g., nanoparticles) provided herein comprise glycyrrhizic acid, also refer to herein as glycyrrhizic acid particles, such as glycyrrhizic acid nanoparticles (GANP).

[0010] In some embodiments, a composition provided herein comprises epigallocatechin gallate (EGCG). In specific embodiments, particles (e.g., nanoparticles) provided herein comprise EGCG.

[0011] In some embodiments, particles (e.g., nanoparticles) provided herein comprise liposome(s).

[0012] In some embodiments, particles (e.g., nanoparticles) provided herein comprise micelle(s).

[0013] In some embodiments, preparation of particles (e.g., nanoparticles) provided herein is achieved through self-assembly. In further or alternative embodiments, preparation of particles (e.g., nanoparticles) provided herein is achieved through thin-film casting. In some embodiments, method of manufacture provided herein include sonication, lyophilization, and / or purification steps.

[0014] In some embodiments, any particles provided herein are formulation in any suitable manner, such as in a nasal or pulmonary formulation. In some embodiments, particles (e.g., nanoparticles) are formulated for metered dose nasal spray delivery.

[0015] In some embodiments, a composition or system provided herein comprises one or more of the plurality of nanoparticle classes described herein. In some instances, separate particle type formulations may be charged within and expelled from separate chambers of a nasal or pul monary spray delivery system. In specific embodiments, the spray delivery system is a nasal spray deliver)’ system. In some instances, such particles are ejected (or administered to an individual) via controlled dose release of each formulation into a combined final mixture and controlled dose mixed release. In some embodiments, a deliver)’ system provided herein comprises a nozzle system suitable for positioning in the middle turbinate. In some embodiments, a deliver)' systemVAZO-701-WO-PCTOlis configured for respiratory and / or CNS / brain deliver}'. In some embodiments, the delivery system is configured for upper turbinate delivery (e.g., via a longer nozzle).

[0016] In some instances, the drug and its components may sequester pathogens in amesoporous matrix reducing entry; damage and or destroy cell membranes; and / or provide systemic protection both from pathogens directly and with added systemic antioxidant support.

[0017] In some embodiments, provided herein is a composition comprising, a first nanoparticle comprising a transition metal and a mucoadhesive. In some embodiments, provided herein is a composition comprising, a first nanoparticle comprising a transition metal; a mucoadhesive; and an optional antioxidant. In some embodiments, provided herein is a composition comprising, a first nanoparticle comprising a transition metal; a mucoadhesive; and an antioxidant. In some embodiments, the composition is a pharmaceutical composition. In various embodiments, such nanoparticles can comprise any suitable substrate system, such as described herein.

[0018] In some embodiments, provided herein is a nasal composition (e.g., nasal spray) comprising, a first nanoparticle comprising a transition metal and a mucoadhesive. In some embodiments, provided herein is a nasal composition (e.g., nasal spray) comprising, a first nanoparticle comprising a transition metal; a mucoadhesive; and an optional antioxidant. In some embodiments, provided herein is a nasal composition (e.g., nasal spray) comprising, a first nanoparticle comprising a transition metal; a mucoadhesive; and an antioxidant.

[0019] In some embodiments, provided herein is a nasal composition (e.g., nasal spray) comprising, a first nanoparticle comprising a transition metal and a mucoadhesive. In some embodiments, provided herein is a nasal composition (e.g., nasal spray) comprising, a first nanoparticle comprising a transition metal; a mucoadhesive; an additional mucoadhesive (e.g., gellen and / or pectin); and an optional antioxidant (e.g., astaxanthin and or quercetin emulsions). In some embodiments, provided herein is a nasal composition (e.g.. nasal spray) comprising, a first nanoparticle comprising a transition metal; a mucoadhesive; and an antioxidant.

[0020] In some embodiments, a composition provided herein comprises a transition metal. In some embodiments, the transition metal is gold, silver, zinc, or an oxide thereof. In some embodiments, a composition provided herein comprises a nanoparticle comprising a transition metal. In some embodiments, the transition metal is physiologically acceptable.

[0021] In some embodiments, a composition provided herein comprises a soft metal. In some embodiments, a composition provided herein comprises a nanoparticle comprising a soft metal. In some embodiments, the soft metal is physiologically acceptable. In some embodiments, the soft metal is bismuth.VAZO-701-WO-PCTOl

[0022] In some embodiments, a composition provided herein comprises a transitional metal and a soft metal. In some embodiments, a composition provided herein comprises a nanoparticle comprising a transitional metal and a soft metal. In some embodiments, a transitional metal and a soft metal are different.

[0023] In some embodiments, a composition provided herein comprises a plant derived component. In some embodiments, a composition provided herein comprises a phyto nanoparticle. In some embodiments, the phyto nanoparticle is physiologically acceptable.

[0024] In some embodiments, a composition provided herein comprises a nanoparticle in any suitable amount, such as in a concentration of about 0.001 mg / mL to about 1 mg / mL. In specific embodiments, the nanoparticle comprises a transitional metal. In more specific embodiments, the nanoparticle comprises a transitional metal and a soft metal.

[0025] In some embodiments, a composition provided herein comprises at least two different nanoparticles (e.g., a first nanoparticle and a second nanoparticle, wherein the first nanoparticle is different from the second nanoparticle). In some embodiments, a composition provided herein comprises a first nanoparticle comprising a transition metal. In some embodiments, a composition provided herein comprises a second nanoparticle comprising a soft metal.

[0026] In some embodiments, a composition provided herein comprises epigallocatechin gallate (EGCG), quercetin, quercetin selenium, carbonized nanogel quercetin selenium, selenium, a seleno-organic compound, or a combination thereof.

[0027] In some embodiments, particles (e.g., nanoparticles) provided herein has any suitable size, such as having an average size of about 0.1 nm to about 250 nm. In some embodiments, particles (e.g., nanoparticles) provided herein has an average size of about 1 nm to about 200 nm. In some embodiments, particles (e.g., nanoparticles) provided herein has an average size of about 100 nm to about 200 nm. In some embodiments, particles (e.g., nanoparticles) provided herein has an average size of about 0.1 nm to about 40 nm. In some embodiments, particles (e.g., nanoparticles) provided herein has an average size of about 1 nm to about 20 nm.

[0028] In some embodiments, a composition provided herein comprises a nanoparticle (e.g., the nanoparticle comprising a transitional metal) having any suitable size, such as having an average size of about 40 nm or less. In some embodiments, a nanoparticle provided herein (e.g., the nanoparticle comprising a transitional metal) has any suitable size, such as having an average size of about 40 nm or less. In specific embodiments, the nanoparticle has an average size of 0.1 nm to about 40 nm. In some embodiments, the nanoparticle has an average size of about 20 nm or less. In specific embodiments, the nanoparticle has an average size of 1 nm to about 20 nm.VAZO-701-WO-PCTOl

[0029] In some embodiments, a composition provided herein comprises a mucoadhesive, such as any suitable mucoadhesive. In some embodiments, the mucoadhesive is a poly a- lysine (PLL), pectin, gellin, PEG, PVA, PVP, poly acry lic acid, poly (hydroxyethyl methacry late), chitosan, chitosan-chondroitin sulfate, hydroxyl ethyl cellulose (HEC), astodrimer sodium, MAEMA, PVA, PVP, poly(acrylic acid) (PAA), poly(methacrylic acid) (PMAA), PLL - PEG - PLGA, hyaluronate, hyaluronic acid, or a combination thereof. In specific embodiments, the mucoadhesive is PLL - PEG - PLGA. In some embodiments, the mucoadhesive is a cellulose or hyaluronate. In some embodiments, the mucoadhesive is a hydroxypropylmethyl cellulose (HPMC).

[0030] In some embodiments, a composition provided herein comprises a poly a- lysine (PLL), pectin, gellin, PEG, PVA, PVP, poly acrylic acid, poly (hydroxyethyl methacrylate), chitosan, chitosan-chondroitin sulfate, hydroxyl ethyl cellulose (HEC), astodrimer sodium, MAEMA, PVA, PVP, poly(acrylic acid) (PAA), poly(methacrylic acid) (PMAA), poly-L-lysine-polyethylene glycol-poly(lactic-co-glycolic acid) (PLL - PEG - PLGA), hyaluronate, hyaluronic acid, or a combination thereof. In specific embodiments, a composition provided herein comprises PLL -PEG - PLGA.

[0031] In some embodiments, a composition provided herein comprises amphiphilic block copolymer, such as hydrophilic poly(2-ethyl-2-oxazoline) (PEtOz) and hydrophobic polyester blocks such as poly(L-lactide) (PLA) (PEtOz-PLA). In some embodiments, a nanoparticle provided herein comprises a micelle comprising amphiphilic block copolymer, such as PEtOz-PLA. [[Are there any other amphiphilic block copolymers you would like to include?]]

[0032] In some embodiments, a composition provided herein comprises an antioxidant, such as any suitable antioxidant. In some embodiments, the antioxidant is a polyphenol. In some embodiments, the antioxidant is a phyto-polyphenol. In some embodiments, the antioxidant comprises quercetin, curcumin, carrageenan, or a combination thereof. In some embodiments, the antioxidant comprises EGCG, GCG, hydroxytyrosol, selenium, glutathione, lithium orotate, beet root, NAD / NMR / NMN. L-theanine, vitamin C, quercetin, quercetageniin, fisetin. apigenin, baicalein, myricetin, an alpha tocopherol, an omega 3 fatty acid, olive oil, lutein, astaxanthin, or a combination thereof. In some embodiments, the antioxidant is L-theanine.

[0033] In some embodiments, a composition provided herein comprises a polyphenol. In some embodiments, a composition provided herein comprises a nanoparticle comprising a polyphenol. In some embodiments, a composition provided herein comprises a phyto-polyphenol. In some embodiments, a composition provided herein comprises quercetin, curcumin, carrageenan, or a combination thereof. In some embodiments, a composition provided herein comprises EGCG,VAZO-701-WO-PCTOlGCG, hydroxytyrosol, selenium, glutathione, lithium orotate, beet root, NAD / NMR / NMN, L-theanine, vitamin C, quercetin, quercetageniin, fisetin, apigenin, baicalein, myricetin, an alpha tocopherol, an omega 3 fatty acid, olive oil, lutein, astaxanthin, or a combination thereof.

[0034] In some embodiments, a composition provided herein comprises a mesoporous silicon.

[0035] In some embodiments, a composition provided herein comprises a graphene oxide.

[0036] In some embodiments, a composition provided herein comprises a compound represented by the following structure:PLL-X -Ywherein,X comprises polyethylene glycol (PEG), methoxy polyethylene glycol (MPEG), hydroxypropyl-gamma-cyclodextrin (HPGCD), hyaluronate, hyaluronic acid, an amino acid (e.g., lysine, arginine, or histidine), or a peptide (e.g.. comprising lysine, arginine, and / or histidine), andY comprises gallinic acid (GA); deacetylated gellan gum (DGG), carboxymethyl cellulose (CMC), hydroxypropyl methyl cellulose (HPMC), or any combination thereof.

[0037] In alternative embodiments. Y comprises gallinic acid (GA); deacet lated gellan gum (DGG), CMC, HPMC, salt diammonium glycyrrhizinate, or any combination thereof. In some instances, the Y is GA (e.g., forming a mucoadhesive matrix). In some embodiments, the mucoadhesive matrix further comprises DGG and / or HA, such as to enhance surface residence and / or local presentation.

[0038] In some embodiments, Y comprises DGG. In some embodiments, Y comprises CMC (e.g., NaCMC). In some embodiments, Y is a gel forming. In some embodiments, Y comprises GA and DGG. In some embodiments, Y comprises GA, DGG, and hyaluronic acid (HA). In some embodiments, Y comprises CMC and HPMC. In some embodiments, Y comprise DGG and CMC.

[0039] In some embodiments, a composition provided herein comprises a nanoparticle comprising epigallocatechin gallate (EGCG). In some embodiments, a composition provided herein comprises a nanoparticle comprising a metal (e.g., a transition metal, such as silver) and epigallocatechin gallate (EGCG). In some embodiments, a composition provided herein comprises a nanoparticle comprising quercetin. In some embodiments, a composition provided herein comprises a nanoparticle comprising an astaxanthin.VAZO-701-WO-PCTOl

[0040] In some embodiments, a composition provided herein comprises one or more nanoparticles comprising a metal and epigallocatechin gallate (EGCG), a quercetin, and / or an astaxanthin. In some embodiments, a composition provided herein comprises one or more nanoparticles comprising at least two components selected from the group consisting of a metal and epigallocatechin gallate (EGCG), a quercetin, and an astaxanthin.

[0041] In some embodiments, a composition provided herein comprises a first nanoparticle comprising a metal and epigallocatechin gallate (EGCG), a second nanoparticle comprising quercetin, and a third nanoparticle comprising an astaxanthin.

[0042] In some embodiments, a composition provided herein comprises a nanoparticle comprising a metal and epigallocatechin gallate (EGCG). In specific embodiments, the metal is gold. In other embodiments, the metal is bismuth. In some embodiments, the metal is silver.

[0043] In some embodiments, a composition provided herein comprises a nanoparticle in any suitable amount, such as in a concentration of about 1 nM to about 100 nM. In specific embodiments, the nanoparticle is in the composition in a concentration of about 5 nM to about 20 nM.

[0044] In some embodiments, the nanoparticles are present in a composition provided herein in a concentration of about 0.2 mg / mL or less. In some embodiments, the nanoparticles are present in a composition provided herein in a concentration of about 0.02 mg / mL or less. In some embodiments, the nanoparticles are present in a composition provided herein in a concentration of about 0.002 mg / mL or less. In some embodiments, the nanoparticles are present in a composition provided herein in a concentration of about 0.0002 mg / mL or less.

[0045] In some embodiments, the nanoparticle present in the composition is in a concentration of about 0.2 ug / mL or less (e.g., when the metal is gold). In some embodiments, the nanoparticle present in the composition is in a concentration of about 0.002 mg / mL or less (e.g., about 0.002 ug / mL or less, such as when the metal is silver). In some embodiments, the nanoparticle present in the composition is in a concentration of about 0.02 ug / mL or less. In some embodiments, the nanoparticle(s) have an (average) size of about 1 nm to about 50 nm. In some embodiments, the nanoparticle(s) have an (average) size of about 5 nm to about 30 nm. In some embodiments, the nanoparticle are present in a composition at a concentration of about 1 ug / mL to about 100 ug / mL, such as about 10 ug / mL to about 100 ug / mL. In some embodiments, the composition or a dose thereof (e.g., a nasal spray unit) comprises about 0.1 mg / kg to about 1 mg / kg of an individual receiving a dose (e.g., in a therapy described in any therapy described herein).VAZO-701-WO-PCTOl

[0046] In some embodiments, a composition provided herein comprises a cyclodextrin. In specific embodiments, the cyclodextrin is a metal cyclodextrin. In some embodiments, a cyclodextrin is a hydroxypropyl cyclodextrin.

[0047] In some embodiments, a composition provided herein comprises a nanogel. In some embodiments, a nanoparticle provided herein comprises a nanogel. In specific embodiments, the nanogel is a carbonized nanogel.

[0048] In some embodiments, a composition provided herein comprises a nanoparticle (e.g., the nanoparticle comprising a quercetin) having any suitable size, such as having an average size of about 100 nm to about 250 nm. In some embodiments, a nanoparticle provided herein (e.g., the nanoparticle comprising a quercetin) has any suitable size, such as having an average size of about 100 nm to about 250 nm. In specific embodiments, the nanoparticle has an average size of about 150 nm to about 170 nm.

[0049] In some embodiments, a composition provided herein comprises EGCG. In some embodiments, the composition comprises EGCG in an amount of no more than 0.04 wt. % EGCG (e.g., 0.01 wt. % to 0.04 wt. %).

[0050] In some embodiments, a composition provided herein comprises a lipid earner. In some embodiments, a nanoparticle provided herein comprises a lipid carrier. In some embodiments, a nanoparticle comprising an astaxanthin comprises a lipid carrier. In specific embodiments, the lipid carrier is a nanostructured lipid carrier (NLC).

[0051] In some embodiments, a composition provided herein comprises a nanostructured lipid carrier (NLC). In some embodiments, a nanoparticle provided herein comprises a nanostructured lipid carrier (NLC).

[0052] In some embodiments, a lipid carrier provided herein (or a nanoparticle comprising the same) has any suitable size, such as having an average (or D99) of about 500 nm or less (e.g., about 250 nm or less or about 0.05 nm to about 500nm). In specific embodiments, the nanostructured lipid carrier has an average (or D99) of about 250 nm or less. In specific embodiments, the nanostructured lipid carrier has an average (or D99) of about 0.05 nm to about 500nm.

[0053] In some embodiments, a composition provided herein comprises a chelating agent. In some embodiments, the chelating agent is ethylenediaminetetraacetic acid (EDTA). In some embodiments, a composition provided herein comprises an ethylenediaminetetraacetic acid (EDTA).VAZO-701-WO-PCTOl

[0054] In some embodiments, a composition provided herein comprises a preservative. In some embodiments, the preservative is benzalkonium chloride (BAK). In some embodiments, a composition provided herein comprises benzalkonium chloride (BAK).

[0055] In some embodiments, a composition provided herein comprises a surfactant. In some embodiments, the surfactant is a polysorbate (e.g., polysorbate 80). In some embodiments, a composition provided herein comprises a polysorbate (e.g., polysorbate 80).

[0056] In some embodiments, a composition provided herein comprises a tonicity adj usting agent. In some embodiments, the tonicity adjusting agent is mannitol. In some embodiments, a composition provided herein comprises mannitol.

[0057] In some embodiments, a composition provided herein comprises a lubricant or moisturizer. In some embodiments, the lubricant or moisturizer is a polyethylene glycol (PEG). In some embodiments, a composition provided herein comprises a polyethylene glycol (PEG).

[0058] In some embodiments, a composition provided herein is a fluid composition, such as a nasal spray. In some embodiments, the fluid composition (e.g., nasal spray) has any suitable viscosity, such as about 50 centipoise (cP) to about 500 cP (e.g., at 0 shear). In some embodiments, the viscosity is about 70 centipoise (cP) to about 3300 cP (e.g., at 0 shear).

[0059] In some embodiments, a composition provided herein comprises water. In some embodiments, a composition is an aqueous composition (e.g., fluid aqueous composition) comprising one or more nanoparticles provided herein (e.g., suspended in the aqueous composition).

[0060] In some embodiments, a composition provided herein comprises hyaluronic acid, pectin, gellen, glycyrrhetinic acid, gallic acid, phenolic acid, methylene blue (e.g., 0.02 wt % or less), d-glutamyl -lysine (DGG). EGCG, a polyphenol, CMC, BAK. polyglycerol SOV4, glutamate, astaxanthin, polyglycerol sulfate, or a combination thereof.

[0061] In some embodiments, a composition provided herein comprises quercetin, beetroot, astaxanthin lithium orotate, span 20, polysorbate (e.g., polysorbate 80), hyaluronate, hyaluronic acid, apgenin silibinin, L-theanine, zinc glycinate, or a combination thereof.

[0062] Provided in certain embodiments herein is a system comprising any composition provided herein, and a device for dispensing a composition to an individual. In some embodiments, the device is suitable for forming droplets of the composition (e.g., aqueous composition), such as a spray device, mist atomizer, or nebulizer. In some embodiments, the device is suitable for forming nasal spray droplets. In certain embodiments, the device is configured to form nasal spray droplets having any suitable droplet size, such as about 1 um to 100 um. In certain embodiments, the deviceVAZO-701-WO-PCTOlis configured to form nasal spray droplets having any suitable droplet size, such as about 10 um to 20 um.

[0063] In some embodiments, provided herein is a method of inhibiting viral absorption and / or proliferation by contacting a virus with any composition or nanoparticle(s) provided herein.

[0064] In some embodiments, provided herein is a method of inhibiting viral absorption and / or proliferation in an individual, the method comprising administering a composition provided herein to the individual. In some embodiments, provided herein is a method of inhibiting viral absorption and / or proliferation in an individual, the method comprising providing any system provided herein (e.g., comprising any composition provided herein), and administering a composition provided herein to the individual. In specific embodiments, administering the composition comprises dispensing a nasal spray from the device (e.g., of the system), such that the composition is administered to the individual intranasally.

[0065] In some embodiments, provided herein is a method of inhibiting viral infection in an individual, the method comprising administering a composition provided herein to the individual. In some embodiments, provided herein is a method of inhibiting viral infection in an individual, the method comprising providing any system provided herein (e.g., comprising any composition provided herein), and administering a composition provided herein to the individual. In specific embodiments, administering the composition comprises dispensing a nasal spray from the device (e.g., of the system), such that the composition is administered to the individual intranasally.

[0066] In certain embodiments, administration of a composition provided herein is achieved using a device configured to form (e.g., nasal spray) droplets having any suitable droplet size, such as about 1 um to 100 um. In certain embodiments, the device is configured to form (e.g., nasal spray) droplets having any suitable droplet size, such as about 10 um to 20 um.

[0067] Provided in certain embodiments herein is a method for reducing absorption and / or proliferation of a virus in an individual, the method comprising administering a composition (e.g., nano-formulation) to the individual, the composition (e.g., nano-formulation) comprising a particle and a lipophilic antioxidant (e g., having a log p value greater than 1, greater than 3, or 3-15).

[0068] Provided in certain embodiments herein is a method for enhancing nanoparticle delivery to an individual, the method comprising administering a composition (e.g., nano-formulation) to the individual, the composition (e.g., nano-formulation) comprising a nanoparticle and a lipophilic antioxidant (e.g., having a log p value greater than 1, greater than 3, or 3-15).VAZO-701-WO-PCTOl

[0069] Provided in certain embodiments herein is a method for treating (e.g., prophylactic treatment) a viral infection in an individual, the method comprising administering a composition (e.g., nano-formulation) to an individual, the composition (e.g., nano-formulation) comprising a particle and a lipophilic antioxidant (e.g., having a log p value greater than 1, greater than 3, or 3-15).

[0070] In some embodiments, a composition provided herein (e.g.. nano-formulation) comprises a mucoadhesive.

[0071] In some embodiments, when a composition provided herein (e.g.. nano-formulation) is administered (e.g., nasally, buccally, sublingually, pulmonary, or topically) to an individual, enhanced nanoparticle delivery' is achieved (e.g., relative to a formulation lacking a lipid antioxidant and / or mucoadhesive).

[0072] In some embodiments, when a composition provided herein (e.g., nano-formulation) is administered (e.g.. nasally, buccally, sublingually, pulmonary, or topically) to an individual, reduced absorption and / or proliferation of a virus is achieved (e.g., relative to a formulation lacking a lipid antioxidant and / or mucoadhesive).

[0073] In some embodiments, when a composition provided herein (e.g., nano-formulation) is administered (e.g., nasally, buccally, sublingually, pulmonary, or topically) to an individual, reduced viral count of a virus (e.g., by reducing absorption and / or proliferation) is achieved (e.g., relative to a formulation lacking a lipid antioxidant and / or mucoadhesive).

[0074] In some embodiments, administration of a composition provided herein (e.g., nanoformulation) to an individual provides anti-viral activity (e.g., against DNA and / or RNA viruses) (e.g., relative to a composition lacking the lipid antioxidant and / or mucoadhesive).

[0075] In some embodiments, a composition provided herein (e.g.. nano-formulation) comprises a plurality of particles (e.g., a plurality of nanoparticles). In some embodiments, the plurality of the particles has an average particle size less than 500 um. In some embodiments, the plurality7of the particles has an average particle size less than 300 um. In some embodiments, the plurality of the particles has an average particle size of about 1 um to 300 um.

[0076] In preferred embodiments, a composition provided herein comprises a plurality of particles, the plurality of particles being a plurality of nanoparticles. In some embodiments, the plurality of the nanoparticles has an average particle size less than 500 nm. In some embodiments, the plurality of the nanoparticles has an average particle size less than 300 nm. In some embodiments, the plurality of the nanoparticles has an average particle size of about 1 nm to 300 nm.VAZO-701-WO-PCTOl

[0077] In some embodiments, a composition provided herein (e.g., nano-formulation) comprises the plurality of the particles formulated as a polymeric capsule (e.g., nanocapsule). In some embodiments, the polymeric capsules comprise a polymeric coat and a lipophilic core. In some embodiments, the lipophilic core comprises (e.g., stabilized with) one or more surfactants (e g., a hydrophilic surfactant and a lipophilic surfactant).

[0078] In some embodiments, a composition provided herein comprises a plurality of particles. In some embodiments, a particle comprises a micelle. In specific embodiments, the micelle comprises amphiphilic poly(2-ethyl-2-oxazoline) poly(lactic acid) PEtOz-PLA diblock copolymer.

[0079] In some embodiments, a polymeric capsule provided herein is prepared using nanoprecipitation.

[0080] In some embodiments, a composition provided herein comprises an antioxidant. In some embodiments, a particle provided herein comprises an antioxidant. In some embodiments, a polymeric capsule provided herein comprises an antioxidant.

[0081] In some embodiments, a composition provided herein comprises an antioxidant and a polymer (e.g., PLGA). In some embodiments, a particle provided herein comprises an antioxidant and a polymer (e.g., PLGA). In some embodiments, a polymeric capsule provided herein comprises an antioxidant and a polymer (e.g., PLGA).

[0082] In some embodiments, a composition provided herein comprises an antioxidant and oil. In some embodiments, a particle provided herein comprises an antioxidant and oil. In some embodiments, a polymeric capsule provided herein comprises an antioxidant and oil.

[0083] In some embodiments, a composition provided herein comprises an antioxidant, polymer (e.g.. PLGA), and surfactant. In some embodiments, a particle provided herein comprises an antioxidant, polymer (e.g., PLGA), and surfactant. In some embodiments, a polymeric capsule provided herein comprises an antioxidant, polymer (e.g., PLGA), and surfactant.

[0084] In some embodiments, a composition provided herein comprises an antioxidant, polymer (e.g., PLGA), oil, and surfactant. In some embodiments, a particle provided herein comprises an antioxidant, polymer (e.g., PLGA), oil, and surfactant. In some embodiments, a polymeric capsule provided herein comprises an antioxidant, polymer (e.g., PLGA). oil. and surfactant.

[0085] In some embodiments, a polymer of a composition provided herein comprises PLGA. In some embodiments, a polymer of a composition provided herein comprises an alpha epsilon poly lysine (PLL).VAZO-701-WO-PCTOl

[0086] In some embodiments, an antioxidant of a composition provided herein comprises a lipophilic antioxidant. In some embodiments, an antioxidant of a composition provided herein comprises a curcuminoid, a polyphenol, a carotenoid, or a tocopherol. In some embodiments, an antioxidant of a composition provided herein comprises astaxanthin. In some embodiments, an antioxidant of a composition provided herein comprises tert-butyl curcumin, demethylated tert-butylated curcumin (lE,6E-l,7-bis(3-tert-butyl-4,5-digydtoxyphenyl)hepta-2,6 / dime-3,5,dione)(DMTC), or demethylated curcumin.

[0087] In some embodiments, a lipophilic antioxidant has a LogP of at least 2.5. In some embodiments, a lipophilic antioxidant has a LogP of at least 6, such as at least 7.5. In some embodiments, a lipophilic antioxidant has a LogP of 6 to 20. In some embodiments, a lipophilic carrier has a LogP of 10-20. In some embodiments, a lipophilic carrier has a LogP of 15-17.

[0088] In some embodiments, a plurality of particles provided herein comprises folic acid modified albumin particles.

[0089] In some embodiments, a composition provided herein comprises chitosan lactate and lactobionic acid (e.g., for use in the targeted treatment of hepatic (liver) pathogens). In some embodiments, a particle provided herein comprises chitosan lactate and lactobionic acid (e.g., for use in the targeted treatment of hepatic (liver) pathogens). In some embodiments, a polymeric capsule provided herein comprises chitosan lactate and lactobionic acid (e.g., for use in the targeted treatment of hepatic (liver) pathogens).

[0090] In some embodiments, a virus provided herein is hepatitis. In some embodiments, a virus provided herein is HEP A-E, CMV, adenovirus, human herpes virus 6, varicella-zoster, or EBV.

[0091] In some embodiments, a plurality of particles provided herein comprises a plurality of liposomes. In some embodiments, a plurality of particles provided herein is a plurality of liposomes. In some embodiments, a plurality of particles provided herein comprises pH-sensitive liposomes. In some embodiments, a plurality of particles provided herein comprises a pH-sensitive excipient and liposomes.

[0092] Provided in some embodiments herein comprises a composition (e.g., nano-formulation) comprising a plurality' of particles and a lipophilic antioxidant (e.g., wherein the lipophilic antioxidant may be incorporated into the plurality of particles or separated therefrom).

[0093] Provided in some embodiments herein comprises a composition (e g., nano-formulation) comprising a plurality of liposomes and a lipophilic antioxidant (e.g., wherein the lipophilic antioxidant may be incorporated into the plurality of liposomes or separated therefrom).VAZO-701-WO-PCTOl

[0094] In some embodiments, a plurality of particles or plurality of liposomes provided herein comprise the lipophilic antioxidant. In some embodiments, a plurality of particles or plurality of liposomes provided herein release the lipophilic antioxidants under acidic conditions. In some embodiments, a plurality of particles or plurality of liposomes provided herein release the lipophilic antioxidants under acidic conditions found at the tissue sites of infectious sequelae (e.g., providing targeted preferential release at the infectious sequelae). In some embodiments, systemic toxicity is reduced (e.g., relative to an otherwise similar formulation, not formulated to comprise a plurality of particles or plurality of liposomes provided herein). In some embodiments, efficacy (e.g., of neutralizing sites) is improved (e.g., relative to an otherwise similar formulation, not formulated to comprise a plurality of particles or plurality of liposomes provided herein). In some embodiments, a plurality of particles or plurality of liposomes provided herein comprise a phospholipid, a cholesterol and a pH sensitive excipient. In some embodiments, a plurality of particles or plurality of liposomes provided herein comprise a pH sensitive excipient that is 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-poly(ethylene oxide) (DSPE-PEOz).

[0095] Provided in some embodiments herein comprises method of preparing a plurality of particles or plurality of liposomes (e.g., provided herein), the method comprising, combining an antioxidant, a polymer, an oil, an organic solvent, and an aqueous phase; evaporating the organic solvent, thereby forming the plurality of particles or plurality of liposomes, wherein the aqueous phase comprises a surfactant and water, and wherein the plurality of particles or plurality of liposomes comprise a polymer coat and a lipophilic core, wherein the lipophilic core comprises the antioxidant.

[0096] In some embodiments, a polymer provided herein comprises PLGA.

[0097] In some embodiments, an oil provided herein comprises labrifil M2125 CS oil, Epikuron E145V.

[0098] In some embodiments, a surfactant provided herein comprises polysorbate (e.g., polysorbate 80), or poloxamer (e.g., poloxamer 407).

[0099] In some embodiments, provided herein is a composition (e.g., any composition provided herein) comprising DGG and hyaluronic acid (or a derivative thereof). In some embodiments, such a composition is formulated for enhanced mucoadhesive gel properties and / or muco-adherence. In some embodiments, the composition is formulated as a nasal spray (e.g., wherein the spray and / or mucoadhesive properties of the spray are enhanced by inclusion of the DGG+hyaluronic acid, such as relative to a composition lacking the DGG+hyaluronic acid). In some embodiments, provided herein is a composition comprising DGG (e g., about 0.5 wt. %) andVAZO-701-WO-PCTOlCMC (e.g., NaCMC) (e.g., about 0.5 wt %). In some embodiments, the composition comprises a lipophilic antioxidant, such as wherein the lipophilic antioxidant has a logP of about 2.5 or more, such as about 5 or more. In some embodiments, the lipophilic antioxidant is astaxanthin, lutein, or glycyrrhizinic acid. In some embodiments, the lipophilic antioxidant is glycyrrhizinic acid (also called glycyrrhizin).

[0100] In some embodiments, provided herein is a particle (e.g., nanoparticle) comprising a pH-sensitive liposomes. In specific embodiments, the pH sensitive liposome comprises one or more silver nanoparticle (e.g., the silver nanoparticle having an average size of less than 50 nm, such as about 10-15 nm), such as wherein the particle is larger than the silver nanoparticles (e.g., at least 5 times as large, at least 10 times as large, or the like, such as having a size provided in any composition provided herein). In some instances, such structures allow for the delivery of trace amounts of silver, such as to provide smart release of silver. In some instances, such a system provides the benefits of silver in a platform with good safety profiles. In some embodiments, provide herein is a composition, such as pharmaceutical composition, comprising a plurality of such particles (e.g., nanoparticles). In specific embodiments, the pharmaceutical composition is a composition formulated for nasal or pulmonary administration (e.g., a nasal spray). In some embodiments, such a composition is used in any suitable method provided herein.

[0101] In some embodiments, provided herein is a particle (e.g., nanoparticle) comprising a metal (e.g., silver) nanoparticle coated with a mesoporous material (e.g., silica). In specific embodiments, the particle is a mesoporous silica-coated silver nanoparticle (e.g., MSPAg-NP). In some embodiments, such a particle has a size as described herein. In some instances, such a platform provides good release of or exposure to the metal, such as to provide the benefits thereof (e.g., anti-viral properties), such as while providing good safety profiles (e.g., by avoiding “peak toxicity” of such a metal). In some embodiments, provide herein is a composition, such as pharmaceutical composition, comprising a plurality of such particles (e.g., nanoparticles). In specific embodiments, the pharmaceutical composition is a composition formulated for nasal or pulmonary administration (e.g., a nasal spray). In some embodiments, such a composition is used in any suitable method provided herein.

[0102] In some embodiments, provided herein is a particle (e.g., nanoparticle) comprising epigallocatechin gallate (EGCG). In some embodiments, the particle (e.g., nanoparticle) comprises EGCG and a metal, such as silver. In specific embodiments, the particle (e.g., nanoparticle) comprises one or more EGCG nanoparticle and one or more smaller metal (e.g., silver) nanoparticle. In some embodiments, the silver nanoparticle(s) have an average size of less than 50 nm, such as about 20 nm. In some embodiments, such particles have an average size ofVAZO-701-WO-PCTOlabout 400 nm to about 500 nm. In some instances, such particles have good stability, lyophilization, and / or manufacturing profiles, such as providing a good platform for commercialization. In some embodiments, provide herein is a composition, such as pharmaceutical composition, comprising a plurality of such particles (e.g., nanoparticles). In specific embodiments, the pharmaceutical composition is a composition formulated for nasal or pulmonary administration (e g., a nasal spray). In some embodiments, such a composition is used in any suitable method provided herein.

[0103] In some embodiments, provided herein is a particle (e.g., nanoparticle) comprising micelles (e.g., comprising amphiphilic block copolymer, such as PEtOz-PLA). In some embodiments, such a particle further comprises quercetin. In some embodiments, the particle has an average size of less than 100 nm, such as about 30 nm. In some embodiments, a composition comprising such particles (e.g., comprising one or more micelle) further comprises particles (e.g., comprising one or more micelle) having an average size of about 1 um. In some instances, such particles having a zeta potential of about 5 and / or have good stability. In some embodiments, provide herein is a composition, such as pharmaceutical composition, comprising a plurality of such particles (e.g., nanoparticles). In specific embodiments, the pharmaceutical composition is a composition formulated for nasal or pulmonary administration (e.g., a nasal spray). In some embodiments, such a composition is used in any suitable method provided herein.

[0104] In some embodiments, provided herein is a particle (e.g., nanoparticle) comprising glycyrrhizic acid. In some embodiments, such particles (e.g., nanoparticles) have an average size of about 100 nm or less, such as about 40 nm to 75 nm. In some embodiments, such particles (e.g., nanoparticles) have an average size of about 500 nm or less. In some instances, such particles increase in size after storage, such as up to about 200 nm after 2 days of cold storage or up to about 300 nm after 10 days of cold storage. In some instances, such particles have a zeta potential of about -30 to about -35. In some instances, such particles having a zeta potential of about 5 and / or have good stability. In some embodiments, provide herein is a composition, such as pharmaceutical composition, comprising a plurality of such particles (e.g., nanoparticles). In specific embodiments, the pharmaceutical composition is a composition formulated for nasal or pulmonary administration (e.g., a nasal spray). In some embodiments, such a composition is used in any suitable method provided herein.BRIEF DESCRIPTION OF THE DRAWINGS

[0105] The novel features of the disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in whichVAZO-701-WO-PCTOlthe principles of the disclosure are utilized, and the accompanying draw ings (also “Figure” and “FIG.” herein) of which:

[0106] FIG. 1A and IB illustrates exemplary SEM image of liposomes without AgNP. FIG. 1C and ID illustrates exemplary SEM image of liposomes with AgNP.

[0107] FIG. 2A illustrates exemplary SEM image of lyophilized GANP without trehalose. FIG.2B illustrates exemplary SEM image of lyophilized GANP with trehalose.

[0108] FIG. 3A and 3B illustrates exemplary SEM image of lyophilized EGCG-NP without any excipient. FIG. 3C and 3D illustrates exemplary SEM image of lyophilized EGCG -NP with trehalose. FIG. 3E and 3F illustrates exemplary SEM image of lyophilized EGCG -NP with trehalose and tween 80. FIG. 3G and 3H illustrates exemplary SEM image of lyophilized EGCG -AgNP with trehalose. FIG. 31 and 3J illustrates exemplary SEM image of lyophilized EGCG -AgNP with trehalose with tw een 80.

[0109] FIG. 4A and 4B illustrates exemplary SEM image of lyophilized diblock copolymer without any excipient. FIG. 4C and 4D illustrates exemplary SEM image of lyophilized diblock copolymer with trehalose.DETAILED DESCRIPTION

[0110] While various embodiments of the invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions may occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed.[OHl] Whenever the term “at least.” “greater than.” or “greater than or equal to” precedes the first numerical value in a series of two or more numerical values, the term “at least,” “greater than” or “greater than or equal to” applies to each of the numerical values in that series of numerical values. For example, greater than or equal to 1, 2, or 3 is equivalent to greater than or equal to 1, greater than or equal to 2, or greater than or equal to 3.

[0112] Whenever the term “no more than,” “less than,” or “less than or equal to” precedes the first numerical value in a series of two or more numerical values, the term “no more than,” “less than,” or “less than or equal to” applies to each of the numerical values in that series of numerical values. For example, less than or equal to 3, 2, or 1 is equivalent to less than or equal to 3, less than or equal to 2, or less than or equal to 1.

[0113] Certain inventive embodiments herein contemplate numerical ranges. When ranges are present, the ranges include the range endpoints. Additionally, every sub range and value within the range is present as if explicitly written out. The term “about” or “approximately” may mean within an acceptable error range for the particular value, which will depend in part on how theVAZO-701-WO-PCTOlvalue is measured or determined, e.g., the limitations of the measurement system. For example, “about” may mean within 1 or more than 1 standard deviation, per the practice in the art. Alternatively, “about” may mean a range of up to 20%, up to 10%, up to 5%, or up to 1% of a given value. Where particular values are described in the application and claims, unless otherwise stated the term “about” meaning within an acceptable error range for the particular value may be assumed.

[0114] In some instances, an aspect of formulations provided herein are their combinations of antiviral elements. In some instances, suitable formulations for effective therapeutic use of such combinations has been elusive. In some instances, provided in certain formulations or compositions herein is the use of scaffolding / lattice large molecules, such as to improve particle (e.g., nanoparticle) retention and delivery. In some instances, such benefits offer important clinical benefits. In some instances, the delivery' of particles (e.g., nanoparticles) provided herein allow the use of a variety of (e.g., aqueous and / or lipophilic) antioxidants. In some embodiments, particles (e.g., nanoparticles) provided in compositions provided herein are combined with transition and / or soft metals. In some embodiments, compositions provided herein allow for the delivery' of agents that avoid 1st pass metabolism and reduce liver and kidney initial absorption and excretion. In some instances, compositions provided herein are administered by any suitable route, such as via nasal, sublingual or injectable routes. In some embodiments, compositions provided herein (e.g., comprising PEG) have reduced immunogenic reactions.

[0115] In some embodiments, formulations provided herein comprising particles (e.g., nanoparticles) described herein (e.g., lipophilic excipients) are suitable for facilitating good absorption (e.g., through the GI tract, nasal cavity’, sinuses, mouth mucosa, or the like). In some embodiments, a composition provided herein is administered by or formulated to be administered by any suitable route, such as nasal - lower / medium (LNT / MNT) vs upper turbinate based on nozzle - degree of penetration to upper nasal cavity' (UNT); sublingual, subcutaneous, suppository (all avoid initial circulation exposure). In some instances, formulations or compositions provided herein facilitate I) delivery of aqueous and (e.g., highly) lipophilic components; 2) provide excellent GI absorption; and / or 3) allow cellular entry yvhere most in vitro data never achieve the needed intracellular phase sufficiently.

[0116] In some embodiments, provided herein are particles (e g., nanoparticles) and compositions comprising such as particles (e.g., nanoparticles). In some embodiments, particles (e.g., nanoparticles) provided herein comprise a continuous matrix, liposome(s), micelle(s), or a combination thereof. In some embodiments, particles (e.g., nanoparticles) provided herein comprise a substrate system (e.g., forming liposomes or micelles). In some embodiments, particles (e.g., nanoparticles) provided herein comprise a substrate system. In specific embodiments,VAZO-701-WO-PCTOlparticles (e.g., nanoparticles) provided herein comprise a substrate system selected from the group consisting of (a) pH-sensitive liposomes, (b) glycyrrhizic acid nanoparticles (GANP), (c) epigallocatechin gallate nanoparticles, (d) mesoporous silica-coated metal nanoparticles (e.g., MSPAg-NP), and (e) micelles (e.g., comprising amphiphilic block copolymer, such as PEtOz-PLA). In various embodiments, any nanoparticles provided herein can comprise any suitable substrate system, such as described herein.

[0117] In some embodiments, particles (e.g., nanoparticles) provided herein comprise a transitional metal (e.g., silver).

[0118] In some embodiments, a composition provided herein comprises a mucoadhesive. In specific embodiments, particles (e.g., nanoparticles) provided herein comprise a mucoadhesive.

[0119] In some embodiments, a composition provided herein comprises an antioxidant. In specific embodiments, particles (e.g., nanoparticles) provided herein comprise an antioxidant.

[0120] In some embodiments, a composition provided herein comprises a quercetin. In specific embodiments, particles (e.g.. nanoparticles) provided herein comprise a quercetin.

[0121] In some embodiments, particles provided herein comprises liposome(s). In some embodiments, the particles comprise pH-sensitive liposome(s). In some embodiments, a pH-sensitive liposome provided herein comprises l,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), cholesteryl-hemisuccinate (CHEMS), l,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), or cholesterol. In some embodiments, a pH-sensitive liposome provided herein comprises 1.2-dioleoyl-sn-glycero-3 -phosphoethanolamine (DOPE), cholesteryl-hemisuccinate (CHEMS), 1.2-distearoyl-sn-glycero-3 -phosphocholine (DSPC), and cholesterol. In some embodiments, such components are provided in any suitable ratio, such as about 4:2:2:2 (molar ratio of DOPE: CHEMS: DSPC: cholesterol).

[0122] In some instances, liposomes are phospholipid-based vesicles useful as drug delivery systems due to their biocompatibility, ability to encapsulate both hydrophilic and hydrophobic compounds, and their tunable physicochemical properties. In some instances, thin-film hydration followed by sonication or extrusion can be used for producing nanoscale liposomes. In some instances, liposomes comprising DOPE, CHEMS, DSPC, and cholesterol can be prepared using thin-film hydration, with pH-sensitive lipid components, such as to improve drug loading and intracellular delivery. In some instances, silver nanoparticles (AgNPs) can be incorporated to enhance antimicrobial or functional properties.

[0123] In some embodiments, particles (e.g., nanoparticles) provided herein comprise glycyrrhizic acid, also refer to herein as glycyrrhizic acid particles, such as glycyrrhizic acidVAZO-701-WO-PCTOlnanoparticles (GANP). In some instances, glycyrrhizic acid (GA) is a naturally occurring saponin with antiviral, anti-inflammatory, and / or immunomodulatory properties. In some instances, its therapeutic potential and / or clinical utility is limited by poor solubility and variable stability7. In some instances, glycyrrhizic acid can self-assemble into GA nanoparticles (GANP) under alkaline hydrothermal conditions, improving solubility, stability, and / or biological activity.

[0124] In some embodiments, particles (e.g., nanoparticles) provided herein comprise epigallocatechin gallate (EGCG). In some embodiments, particles (e.g., nanoparticles) provided herein comprise a metal (e.g., a transition metal, such as silver) and epigallocatechin gallate (EGCG). In some instances, epigallocatechin gallate (EGCG) is a bioactive polyphenol with antioxidant and / or therapeutic properties, but may have poor stability7and / or limited bioavailability. In some instances, forming nanoparticles through amino acid-assisted assembly may enhance its structural stability and / or functionality. In some instances, glycine-based EGCG nanoparticles (EGCG-NP) can provide a simple and effective platform that can incorporate metallic components such as silver, enhancing antimicrobial and / or functional performance.

[0125] In some embodiments, particles (e.g., nanoparticles) provided herein comprise a transitional metal (e.g., silver) coated with a mesoporous material (e.g.. silica or silicon). In specific embodiments, particles (e.g., nanoparticles) provided herein comprise a transitional metal (e.g., silver) coated with mesoporous silica. In some instances, silver nanoparticles (AgNPs) may display antimicrobial properties because they can release Ag+ions, produce reactive oxygen species, and / or damage bacterial membranes. In some instances, uncoated AgNPs may have undesired characteristics, such as instability, aggregation, and / or uncontrolled oxidation, which may limit their practical use. In some instances, mesoporous silica coatings can enhance nanoparticle stability7, regulate ion release, and / or allow surface functionalization for advanced uses.

[0126] In some embodiments, particles (e.g., nanoparticles) provided herein comprise micelle(s). In some embodiments, particles (e.g., nanoparticles) provided herein comprise amphiphilic block copolymer, such as hydrophilic poly(2-ethyl-2-oxazoline) (PEtOz) and hydrophobic polyester blocks such as poly(L-lactide) (PLA) (PEtOz-PLA). In some embodiments, particles (e.g., nanoparticles) provided herein comprise a micelle comprising amphiphilic block copolymer, such as PEtOz-PLA. In some instances, amphiphilic diblock copolymers comprising hydrophilic poly(2-ethyl-2-oxazoline) (PEtOz) and hydrophobic polyester blocks such as poly(L-lactide) (PLA) may be used for drug delivery and nanocarrier applications. In some instances, PEtOz-PLA copolymers can be synthesized via ring-opening polymerization of L-lactide initiated byVAZO-701-WO-PCTOlhydroxyl-terminated PEtOz. In some instances, the ratio between lactide and PEtOz may influence block length, hydrophilic-hydrophobic balance, and / or micelle formation.

[0127] In some embodiments, provided herein are compositions (e.g., pharmaceutical or nutraceutical compositions) comprising any nanoparticle provided herein. In some embodiments, such compositions are formulated in any suitable manner. In specific embodiments, compositions provided herein comprising a nanoparticle provided herein is formulated for nasal, oral, pharyngeal, pulmonary, sublingual, or ophthalmic administration, such as described herein.

[0128] In some embodiments, such compositions and particles provided herein are used in any suitable manner, such as a method described herein.

[0129] In some embodiments, a composition provided herein comprises an emulsion, which may have advantages for homogeneous delivery of lipid and hydrophilic excipients. In some instances, emulsions are less clinically effective due to either being more toxic due to providing larger size particles, lesser absorption, and in terms of efficacy lower duration. In some embodiments, provided herein are compositions having particles (or nanoparticles), such as having an average particle size of less than 500 um. In some embodiments, the particles (or nanoparticles) have an average size of less than 300 um. In some instances, particles or nanoparticles are described herein as comprising one or more agent. It should be understand that such disclosure includes disclosure includes disclosure of the other of the particles or nanoparticles (for example, disclosure of a nanoparticle comprising a specific agent includes disclosure of a particle comprising the specific agent).

[0130] In some embodiments, particles (e.g., nanoparticles) provide herein having any average size of less than 1000 nm (e.g., 0.1 nm to 1000 nm). In some instances, particles (e.g., nanoparticles) provided herein have an average size of less than 500 nm. In specific embodiments, the particles (e.g., nanoparticles) have an average size of less than 300 nm. In more specific embodiments, the particles (e g., nanoparticles) have an average size of less than 200 nm. In still more specific embodiment, the nanoparticles have an average size of less than 20 nm.

[0131] In some embodiments, particles (e.g., nanoparticles) provided herein has any suitable size, such as having an average size of about 0.01 nmto about 500 um. In some embodiments, particles (e.g., nanoparticles) provided herein has an average size of about 1 nm to about 200 nm. In some embodiments, particles (e.g., nanoparticles) provided herein has an average size of about 100 nm to about 200 nm. In some embodiments, particles (e.g., nanoparticles) provided herein has an average size of about 0.1 nm to about 40 nm. In some embodiments, particles (e.g., nanoparticles) provided herein has an average size of about 1 nm to about 20 nm.VAZO-701-WO-PCTOl

[0132] In some embodiments, compositions provided herein comprise phyto based (e.g., nano) particles, such as particles that are derived from combining polyphenols / polyphenol catechol. In some instances, such particles add a much safer option for particles (e.g., nanoparticles) particularly with metals where oxides can be more toxic. In some instances, compositions provided herein, through the use of various combinations described herein, provided improved delivery and reduced immunogenicity risk. In some embodiments, combinations provided herein act to 1) retard viral absorption (e.g., through barrier molecular structure adhesive) through nasal mucosa, 2) retard viral absorption (e.g., through barrier molecular structure adhesive) through pharyngeal or sublingual mucosa or surfaces, 3) deactivate viral membranes (e.g., slowed or trapped through mucosal barrier during any egress with mixed + and - charges diffusing significant integrity of viral particles and both reducing load that penetrates into systemic circulation), 4) disable or weaken virus replication, and / or 5) destroy viral particles. In some instances, compositions provided herein ameliorate or clinically largely prevent the cytokine storm associated with successful cell replication and destruction.

[0133] In some embodiments, provided herein are methods of providing (e.g., broad-based DNA / RNA) antiviral prophylaxis and / or (e.g., early) treatment. In some instances, formulations provided herein inhibit or protect against viral infection or severity' of infection through several mechanisms.

[0134] In some instances, compositions provided herein are administered by and / or formulated for administration by (e.g., systemic first pass or local delivery via spray) nasal administration (e.g., low-mid LNS, MNS; upper UNS), pharyngeal administration (e.g., by inhaler), pulmonary' administration (e.g., by nebulizer), sublingual administration (e.g.. by drops / gel). ophthalmic administration (e.g., by eye drops). In some instances, such formulation allows for longer effective duration and reduced immune cell targeting.

[0135] In some instances, compositions provided herein are formulated to enhance ability to inactivate individual and or in many cases weaken entire classes of viruses and or microbials.

[0136] In some instances, compositions provided herein comprise a combination of excipients designed to target antimicrobial weakness, damage and or destruction. In some instances, such effects are achieved via; i) barriers to host penetration; ii) destruction via web-like entrapment and cell membrane weakening or lysis; iii) viral destruction on invasion, thereby reducing viral load; iv) weaken or bind host antigens to formulation components to reduce or eliminate immunogenicity; v) sufficiently thwarting antimicrobial invasion to minimize, delay, and or overtly thwart untoward in flam mat ory response rendering cytokine storm sequelae and or cerebral inflammatory' “long Covid” and related cerebral infectious chronic effects eliminated or substantially reduced; vi) taken prophylactically the nearly ubiquitous attacks on antimicrobialsVAZO-701-WO-PCTOlrenders their successful invasion and morbidity virtually eliminated as a pandemic or large scale societal threat for most pathogens.

[0137] In some embodiments, methods provided herein facilitate CNS penetration, such as via upper nasal turbinate (UNT), sublingual delivery, and systemic oral, rectal, or subcutaneous injection delivery. In some instances, such methods facilitate reduction of pandemic acceleration of vectors into societal contagion.

[0138] In some instances, compositions provided herein facilitate CNS penetration, such as via primarily UNS or sublingual delivery or systemic, such as to reduce inflammatory neurological conditions such as multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), or other neurological degenerative inflammatory conditions.

[0139] In some embodiments, compositions provided herein are administered to an individual to provide antibacterial (e.g., against resistant strep, MRSA staphylococcus), antifungal (e.g., fusarium), antiprotozoal (e.g., acanthamoeba) (e.g.. prophylactic) treatment. In some embodiments, compositions provided herein are administered to an individual to provide (e.g., prophylactic) treatment for rare contagion viral threats such as EBOLA and Dengue fever may be effectively prevented as well.

[0140] In some embodiments, any method of (e.g., prophylactic) treatment provided herein comprises a method of administering a composition or formulation provided herein, such as by any route described herein.

[0141] In some instances, combinations provided herein can reduce microbial infection, from mild to contagion via reduced penetration; structural weakening; attenuated virulence and replication: ameliorated cytokine storm or excessive inflammation; penetrate microbial biofilms, maintain effectiveness as microbials mutate to variants. In some instances, long Covid and other cerebral sequelae, and general debilitation from pulmonary inflammatory fibrosis are targeted for therapeutic benefit. In some instances, compositions provided herein limit microbial system entry via combinations of one or more mucoadhesive, three-dimensional lattice adherent mucosal barrier protection; sub 20 nM mucosal adhesive particle inactivators; reduced viral attachment and penetration; enhanced blood brain barrier resistance; enhanced blood brain and systemic response to cytokine dissemination; enhanced T cell kill response and / or microbial inactivation.

[0142] In some instances, compositions provided herein are antiviral and / or antimicrobial, while maintaining a degree of (e.g., local) autophagy when administered.

[0143] In some embodiments, a composition provided herein comprises a transition metal (or oxide thereof) or soft metal. In some embodiments, a composition provided herein comprises a transition metal. In some embodiments, a composition provided herein comprises a soft metal.VAZO-701-WO-PCTOl

[0144] In some embodiments, a particle (e.g., nanoparticle) provided herein comprises a transition metal (or oxide thereof) or soft metal. In some embodiments, a particle (e.g., nanoparticle) provided herein comprises a transition metal. In some embodiments, a particle (e.g., nanoparticle) provided herein comprises a soft metal.

[0145] In some embodiments, a soft metal (e.g., of a composition or particle provided herein) is any suitable soft metal, such as silver, gold, or zinc. In some embodiments, the soft metal is bismuth, antimony, platinum, or copper. In specific embodiments, the soft metal is bismuth. In embodiments, soft metal is present (e.g., in the composition or particle) in any suitable amount, such as about 10 ug / mL or less, such as 5 ug / mL or less, 2 ug / mL or less, 1 ug / mL or less, or 0.5 ug / mL or less. In some embodiments, the soft metal (e.g., in a composition or particle provided herein) is combined with sialic acid (e.g., with gold or silver).

[0146] In some embodiments, a transition metal (e.g., of a composition or particle provided herein) provided herein is any suitable transition metal, or oxide thereof. In some embodiments, the transition metal is platinum, copper, gold, or silver. In some embodiments, a transition metal is a phyto derived transition metal, such as in the form of a phyto derived particle (e.g., nanoparticle). In some embodiments, the transition metal is combined with a polyphenol, such as when being phyto derived. In some instances, the presence of a polyphenol can facilitate reduction in toxicity of transition metals (e.g., oxides thereof).

[0147] In some embodiments, compositions (or particles thereof) comprising transition metals and / or soft metals have antimicrobial properties. In some instances, the antimicrobial action of these compositions (e.g., particles, such as nanoparticles, thereof) is based on one or more of four different mechanisms, such as operating simultaneously. In some instances, such mechanisms may include adhesion of the metal (e.g., nanoparticles comprising the same) onto a cell membrane, penetration of the metal (e.g., nanoparticles thereof) inside the microorganism (e.g., bacteria) to induce damage of the intracellular parts, oxidative stress caused by the production of reactive oxygen species and / or modulation of the signal transduction pathways of the microorganism (e.g., bacteria).

[0148] In some embodiments, compositions (or particles thereof) provided herein comprise two or more metals (e.g., two or more transition metals, two or more soft metals, or one or more soft metal and one or more transition metal). In some embodiments, compositions (or particles thereof) provided herein comprise silver and bismuth. In some embodiments, compositions (or particles thereof) provided herein comprise gold and bismuth. In some embodiments, compositions (or particles thereof) provided herein comprise silver and gold. In some embodiments, a composition provided herein comprises Ag-Bi Phyto NP; Au-Bi Phyto NP; or Ag-Au Phyto NP.VAZO-701-WO-PCTOl

[0149] In certain embodiments, compositions (or nanoparticles thereof) comprise additional components or excipients. In some instances, such additional components or excipients may facilitate improved antimicrobial (e.g., antiviral activity ), such as relative to an otherwise identical composition not comprising the additional component or excipient. In some embodiments, compositions (or nanoparticles thereof) comprise a stabilizing excipient, such as glycine. In some embodiments, compositions (or nanoparticles thereof) comprise glycine. In some embodiments, compositions (or nanoparticles thereof) comprise cryoprotectant. In specific embodiments, compositions (or nanoparticles thereof) comprise trehalose. In some instances, presence of such cryoprotectant(s) may maintain size integrity and / or prevent aggregation of the particles.

[0150] In some embodiments, provided herein are compositions (or nanoparticles thereof) provided herein comprise EGCG; Quercetin, carbonized nanogel, quercetin, selenium, or an organic selenium compound (e.g., ebselen or an analog thereof).

[0151] In some embodiments, a composition (or nanoparticle thereof) provided herein comprises an antioxidant, such as a hydrophilic antioxidant, a lipophilic antioxidant, or a combination thereof. In some instances, presence of such antioxidant(s) may' facilitate suppression of cytokine storm. In some embodiments, the size of particles or nanoparticles provided herein can be measured by any suitable method, such as Dynamic Light Scattering (DLS) and Malvern Zetasizer Nano-ZS. In some embodiments, the size of particles or nanoparticles provided herein is measured by Dynamic Light Scattering (DLS). In some embodiments, the size of particles or nanoparticles provided herein is measured by Malvern Zetasizer Nano-ZS.

[0152] In some embodiments, particles or nanoparticles provided herein have any suitable size, such as less than 500 um. In some embodiments, particles or nanoparticles provide herein have a size (e.g., an average size) of less than 300 um. In some embodiments, particles or nanoparticles provide herein have a size (e.g., an average size) of 100 to 300 um. In some embodiments, particles or nanoparticles provide herein have a size (e.g., an average size) of less than 500 nm. In some embodiments, particles or nanoparticles provide herein have a size (e.g., an average size) of less than 300 nm. In some embodiments, particles or nanoparticles provide herein have a size (e.g.. an average size) of 100 to 300 nm. In some embodiments, particles or nanoparticles provide herein have a size (e.g., an average size) of about 50 nm or less. In some embodiments, particles or nanoparticles provide herein have a size (e.g., an average size) of about 40 nm or less. In some embodiments, particles or nanoparticles provide herein have a size (e.g., an average size) of about 20 nm or less. In some instances, smaller particle sizes may provide reduced toxicity and / or greater antimicrobial efficacy. In some instances, bimetal particles or nanoparticles may be larger (e.g., due to the inclusion of multiple metals), but improved efficacy and / or reduced toxicity7may result relative to mono-metal particles of a similar size.VAZO-701-WO-PCTOl

[0153] In some embodiments, compositions (or particles thereof) provided herein comprise one or more phyto element (element derived from a plant source). In some instances, a composition provided herein comprises a phyto particle (or nanoparticle), such as comprising a metal comprising a polyphenol ligand.

[0154] In some embodiments, compositions (or particles thereof) provided herein comprise a mucoadhesive. In some embodiments, presence of a mucoadhesive facilitates diffusion of charged components, such as into a mucosa to which the composition is administered. In some instances, the net charge of a composition provided herein is near zero or zero. In some instances, overall charge of the composition is optimized to facilitate optimal or desired component (e.g., particle) penetration to / into the mucosa. In some instances, overall charge of the composition is optimized to facilitate optimal or desired component (e.g., particle) release (e.g., slow release) to / into the mucosa.

[0155] In some instances, use of a mucoadhesive can add a barrier to penetration for microbial (e.g., viral) particles. In some instances, the composition allows component (e.g., particle) penetration for anti -microbial (e.g., anti-viral activity) (e.g., providing antiviral prophylaxis and / or reduced viral virulence). In some instances, presence of a mucoadhesive provides prolonged drug retention to mucosa (e.g., relative to an otherwise identical composition lacking the mucoadhesive). In some instances, the composition provides, slow-release absorption (e.g., slower relative to a composition lacking the mucoadhesive).

[0156] In some embodiments, a nanoparticle provided herein comprises mesoporous silica (e.g., on the surface of the particle) and a mucoadhesive. In some instances, the mucoadhesive silica can act as a payload reservoir and / or a stabilizer (e.g., for lipophilic antioxidants). In some instances, combining mesoporous silica with a mucoadhesive provides such benefit(s) along with improved residence time.

[0157] In some embodiments, a particle provided herein comprises poly(lactic-co-glycolic acid (PLGA), such as providing a matrix within the particle. In some embodiments, particle further comprises a mucoadhesive, such as a polylactic acid (PLA). In some embodiments, the particle comprises a surface coating, such as comprising chitosan or hyaluronic acid (HA).

[0158] In some embodiments, a particle provided herein comprises an agent to reduce mucoadhesive or improve mucus-penetration, such as polyethylene glycol (PEG). In some embodiments, a composition provided herein (e.g.. for nasal administration) comprises such an agents, such as to improve epithelial access.

[0159] In some embodiments, the mucoadhesive is gellan gum, DGG; pectin; chitosan (or a salt or derivative thereof); HPMC (or a salt or derivative thereof); hyaluronic acid; a carbomer, aVAZO-701-WO-PCTOlpoly acryl ic acid), a carbopol (or a salt or derivative thereof); a Poloxamer; or any combination thereof.

[0160] In some embodiments, a mucoadhesive provided herein comprises a scaffolding / lattice structure, such as provided by a Poly a- Lysine (PLL). In some instances, a composition provided herein comprises PLL, such as (e.g., high MW) PLL forming a large lattice like but porous barrier. In some instances, the multiple charged moieties of a matrix may further improve antimicrobial activity of a composition provided herein, while facilitating mucosa penetration of components of the composition.

[0161] In some embodiments, a mucoadhesive provided herein comprises Chitosan; Alginate; Pectin; Gelatin; Gellin, Hyaluronic acid; Guar Gum; Xanthan Gum;Carrfageenan; PVA, PAA (polyacrylic acid); Carbopol (viscosityO; PEG; PVP, HPMC,Thiolated polymers of the above; Fibrin, collagen, elastin; lecithin, phospholipids; catecholmodified polymers; or Poly dopamine.

[0162] In some embodiments, a composition provided herein comprises polyethylene glycol (PEG). In some embodiments, compositions provided herein comprise lectins, thiolated polymers, or a combination thereof.

[0163] In some embodiments, a mucoadhesive provided herein is pectin, gellin, polyethylene glycol (PEG), polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), poly acrylic acid (PAA), poly hydroxyethyl methacrylate (HEMC). chitosan, chitosan-chondroitin sulfate, hydroxyl ethyl cellulose (HEC), astodrimer sodium; poly-L-lysine (PLL), poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA), Poly(lactic-co-gly colic acid) (PLGA), PLL-PEG, PLL-PEG-PLGA, or a combination thereof.

[0164] In some embodiments, a mucoadhesive provided herein comprises PLL-X -Y, wherein X is PEG, rnPEG, 2-Hydroxypropyl-gamma-cyclodextrin (HPGCD), hyaluronic acid, an amino acid (e.g., positively charged amino acid), a peptide, lysine arginine, histidine, and wherein Y is Ga+, Ga+DGG+Hyaluromc acid, CMC, HPMC, or CMC-HPMC.

[0165] In some embodiments, a composition (or nanoparticle thereof) comprises an antioxidant. In some embodiments, a composition (or nanoparticle thereof) comprises a hydrophilic antioxidant. In some embodiments, a composition (or nanoparticle thereof) comprises a lipophilic antioxidant. In some embodiments, a composition (or nanoparticle thereof) comprises a hydrophilic antioxidant and a lipophilic antioxidant.

[0166] In some instances, antioxidants, such as polyphenols, have several potential benefits. In some instances, antioxidants, such as phyto polyphenol catechols, can provide good tolerability when administered with a transition metal (e.g., nanoparticle thereof). In some instances, use of such agents can facilitate prevention or amelioration of cytokine storm and / or provide systemic and / or cerebral anti-inflammatory protection.VAZO-701-WO-PCTOl

[0167] In some embodiments, a lipophilic antioxidant comprises quercetin, curcumin, or carrageenan. In some instances, such antioxidants are notable for their strong lipophilic antioxidant potential. In some instances, lipophilic antioxidants facilitate suppression of T cell scavenging autophagy (e.g., relative to otherwise identical compositions lacking the lipophilic antioxidant(s)). In some instances, a composition provided herein comprises a lipophilic and a hydrophobic antioxidant. In some instances, hydrophilic and hydrophobic antioxidant combinations can provide greater benefit (e.g., relative to otherwise identical compositions lacking both a lipophilic antioxidant and a hydrophilic antioxidant). In some instances, such a combination can provide good cytoplasmic and mitochondrial reduced ROS generation potential and / or lipophilic cell membrane reduced inflammatory infiltration. In some instances, combinations of a lipophilic antioxidant and a hydrophilic antioxidant can provide reduced virulence and morbidity (e.g., pulmonary' cytokine storm of Sars 2, etc.), such as relative to otherwise identical compositions lacking both a lipophilic antioxidant and a hydrophilic antioxidant.

[0168] In some embodiments, a lipophilic antioxidant comprises quercetin, quercetagetin, fisetin, apigenin, baicalein (GI hydrolysis, high first pass metabolism), myricetin, alpha tocopherols (Vit E derivatives), omega 3 fatty acids, olive oil, lutein, or astaxanthin. In some embodiments, a lipophilic antioxidant comprises astaxanthin.

[0169] In some embodiments, compositions (or nanoparticles thereof) comprise carbonized nanogels (CNG). In some instances, CNGs provide a similar structural antiviral opportunity as transition metals, with less toxicity. In some instances, use of low' temperature (e.g., ~ 270 C) pyrolysis provides a mild carbonization process that can promote formation of gel-like structures cross-linked with an antioxidant. In some instances, compositions comprising CNG and antioxidant, such as a quercetin and / or astaxanthin, (e.g., according to any description provided herein) can demonstrate improved antimicrobial (e.g., antiviral) properties (e.g., relative to otherwise similar compositions lacking a CNG.

[0170] In some embodiments, a hydrophilic antioxidant comprises EGCG, GCG. hydroxytyrosol, selenium, glutathione, lithium orotate, beet root, NAD / NMR / NMN, L-theanine, or Vit C.

[0171] In some embodiments, a composition provided herein comprises a nanoparticle comprising an antioxidant. In some embodiments, the antioxidant-containing nanoparticle comprises additional components of the composition. In certain embodiments, the composition comprises an antioxidant-containing nanoparticle and another nanoparticle comprising one or more additional nanoparticle of a system provided herein.

[0172] In certain embodiments, a composition provided herein comprises one or more nanoparticles. In some embodiments, a composition provided herein comprises at least twoVAZO-701-WO-PCTOldifferent nanoparticles (e.g., wherein the two different nanoparticles comprise at least one different component than the other nanoparticle). In some embodiments, for example, a first nanoparticle comprises a mucoadhesive and a second nanoparticle comprises a metal (e.g., a transitional metal and / or a soft metal).

[0173] In some embodiments, a composition provided herein comprises a nanoparticle comprising one or more antioxidant (e.g., having an average size of about 1 nm to about 500 nm). In some embodiments, a composition provided herein comprises a nanoparticle comprising astaxanthin (e.g., having an average size of about 1 nm to about 200 nm, such as about 142 nm). In some embodiments, a composition provided herein comprises a nanoparticle comprising baicalein (e.g., having an average size of about 1 to about 300 nm, such as about 285 nm). In some embodiments, a composition provided herein comprises a nanoparticle comprising chitosan. In some embodiments, a composition provided herein comprises a nanoparticle comprising lecithin.

[0174] In some embodiments, a composition provided herein comprises a nanoparticle comprising a polyphenol (e.g., a catechols), such as comprising phyto nanoparticle carrier.

[0175] In some embodiments, a composition provided herein comprises a nanoparticle comprising a flavonoid.

[0176] In some embodiments, a composition provided herein comprises a nanoparticle comprising epigallocatechin-3 gallate (EGCG), such as to improve stability and absorption.

[0177] In some embodiments, compositions provided herein are administered using any suitable method, such as nasal administration. In some instances, nasal administration can avoid 1stpass liver metabolism and / or GI hydrolysis.

[0178] In some embodiments, compositions provided herein comprise PEG-PLGA EGCG nanoparticles, Au-EGCG nanoparticles, Bi-EGCG; Bi-HP-B-CD (hydroxypropyl-Beta-cyclodextrin), EGCG Phyto nanoparticles.

[0179] In some embodiments, compositions (or nanoparticles thereof) comprise chitosan, chitosan -chondroitin, polysorbate (e.g., polysorbate 80), or poloxamer (e.g., poloxamer 407).

[0180] In some embodiments, a composition provided herein is administered in a method provided herein by any suitable route. In some embodiments, a composition provided herein is administered by nasal administration (e.g., NASAL LNT MNT (SYSTEMIC) / UNT (BBB)), pharyngeal administration, ophthalmic administration, sublingual administration, suppository' administration, or oral administration. In some embodiments, nasal administration is achieved by¬ spray, drop, inhalation drop, or powered spray. In some embodiments, pharyngeal administration is administered by spray or drop. In some embodiments, ophthalmic administration is achieved by use of drop. In some embodiments, sublingual administration is achieved by drop or dissolvableVAZO-701-WO-PCTOlor disintegrable dosage form (e.g., gel film, pellet, or tablet). In some embodiments, oral administration is achieved by use of a enterically (or GI) coated form.

[0181] In some embodiments, a composition (or nanoparticle thereof) provided herein comprises a mesoporous silicone particle, GO GOQD, an Organotin, a B-cyclodextrin, hyaluronic acid, polyglycerol SO4, glutamate, GA+, PLL (ep / alpha), Ga, Ga+DGG+CM, Quer, Asta, Fisetin, SBO, Aligenin, or Myrecetin.

[0182] In some embodiments, a composition (or nanoparticle thereof) provided herein comprises acetate.

[0183] In some embodiments, a composition (or nanoparticle thereof) provided herein comprises PLL-HPCD. In some embodiments, a composition (or nanoparticle thereof) provided herein comprises antiviral nutraceuticals, anionic cationic charges (e.g., that can lyse viral membranes), a hydrophilic component, a lipophilic component, or a combination thereof.

[0184] In some embodiments, a composition provided herein comprises a viscosity enhancing agent. In some embodiments, a composition provided herein has a non-linear viscosity.

[0185] In some embodiments, a composition provided herein is or is formulated with a Nasal Spray (e.g., LNT, MNT* UNT*), a nasal gel, a droplet spray, inhaled drops, sublingual drops, sublingual gel, sublingual dissolving tablet, optic drops, nebulized spray, a metered dose inhaler, pharyngeal spray, subcutaneous injection, capsule, oral gel (optionally GI coated), cutaneous patch (e g., with slow release), rectal suppository.

[0186] In some instances, routes of administration provided herein attack points of antimicrobial and particularly viral entry, via mucosal nasal, pharyngeal (throat), ocular and otic surfaces, attack organs of most serious early pathology (e.g., brain (via MNT and particularly UNT nasal spray). In some embodiments compositions provided herein are administered by oral inhalative administration, via nebulizers, or metered-dose inhalers. In some embodiments compositions provided herein are administered by nebulizers include jet, ultrasonic, or vibrating.

[0187] In some embodiments, a composition provided herein comprises at least one component from Table 1. In some embodiments, the composition comprises at least one component from column A. In some embodiments, the composition comprises at least one component from column B. In some embodiments, the composition comprises at least one component from column C. In some embodiments, the composition comprises at least one component from column A and at least one component from column B. In some embodiments, the composition comprises at least one component from column A and at least one component from column C. In some embodiments, the composition comprises at least one component from column B and at least one component from column C. In some embodiments, the composition comprises at least one component from column A, at least one component from column B, and at least one component from column C.VAZO-701-WO-PCTOlTable 1:

[0188] In some embodiments, provided herein are methods of (e.g., prophylactically) treating a viral infection, the method comprising administering a composition provided herein to an individual (e.g., in need thereof), such as by any suitable route (e.g., as described herein). In some embodiments, the viral target is SARS, COVID, corona virus, MERS, influenza, Bird Flu, H1N1, adenovirus, RSV, HIV, hepatitis A, hepatitis B, hepatitis C, polio, rubeola, varicella, HSV-1, HSV-2, EBV, norovirus, coxsackievirus (HFMD and related infections), or any combination thereof.

[0189] In some embodiments, provided herein are methods of (e.g., prophylactically) treating a microbial infection, the method comprising administering a composition provided herein to an individual (e.g., in need thereof), such as by any suitable route (e.g.. as described herein). In some embodiments, the microbial target is MRSA (Methicillin Resistant Staphaloccus Aureus), K. pneumoniae, C. albicans, S. Typhimuriam, P. aeruginosa, E. coli, B. cerus, typhus, or any combination thereof.

[0190] In some embodiments, a nanoparticle provided herein is a nanoemulsion particle or a nanocapsule particle. In some embodiments, the nanoparticle has a particle size of about 0.1 nm to about 50 nm. In certain embodiments, the nanoparticle has a particle size of about 10 nm to about 50 nm. In some embodiments, the nanoparticle has a particle size of about 5 nm to about 25 nm. In some embodiments, the nanoparticle has a particle size of about 10 nm to about 15 nm.

[0191] In some embodiments, a nanoparticle (e.g.. nanoemulsion or nanocapsule nanoparticle) comprises Ag - quercetin, and or Ag-pyrithione. In some instances, nanoemulsion complexes of Ag - quercetin, and or Ag-pyrithione are formed and / or used. In some embodiments, transitionon metal oxide complexes are formed and / or used, e.g., via Phyto mediated processes.

[0192] In some embodiments, a nanoparticle (e.g.. nanoemulsion or nanocapsule nanoparticle) comprises selenium. In some embodiments, selenium containing-nanoparticles (e.g., nanoemulsions) are created by one or more of: Selenium crystalline nanostructures via hydrothermal methods, Selenium crystalline nanostructures via sodium selenite precursor and a reducing agent, Selenium nanoparticles using templates, including PEG200, SeleniumVAZO-701-WO-PCTOlnanoparticles use a polysaccharide template method, Selenium nanoparticles are synthesized via one or more of chitosan, hyaluronic acid, polyethyleneimine, and ferulic acid, Selenium nanoparticles via a laser ablation method, Selenium nanoparticles synthesized via Phyto extract admixture of Selenium Selite, CS chitosan glycerol phosphate selenium nanoparticles. Selenium nanoparticles use chemical methods of reduction, e.g. ascorbic acid, Selenium hydrothermal method: ascorbic acid as reducer and stabilizer with Na2SeO3 as a precursor, or Coffee bean extract reduction of Na2SeO3 Se NP, N2H6VC12 used as reducing agent.

[0193] In some embodiments, a composition provided herein comprises a viscosity enhancing agent, such as Methocell E4M-M4 orHPMC (e.g., at concentration ranges from 0.25% to 1.75%).

[0194] In some embodiments, a composition provided herein further comprises a chelating agent, such as edetate (e.g., at about 0.1%), such as to reduced metal surface contamination.

[0195] In some embodiments, a composition provided herein is used for the prophylaxis and / or treatment of simultaneous exposure to one or more viral etiologies and one or more bacterial secondary infection, such as Influenza or Covid infection with secondary pneumococcal pneumonia or a viral infection with secondary bacterial infection.

[0196] In some embodiments, a composition provided herein is used (e.g., by administering to an individual, such as in need thereof) to ameliorate or reduce plaque formation of Alzheimer, or cerebral inflammation. In some embodiments, a composition provided herein is used (e.g., by administering to an individual, such as in need thereof) to alleviate a neurological condition such as multiple sclerosis (MS). In some embodiments, a composition provided herein is used (e.g., by administering to an individual, such as in need thereof) to alleviate Amyotrophic Lateral Sclerosis (ALS). In some embodiments, a composition provided herein is used (e.g., by administering to an individual, such as in need thereof) to reduce severity and improve the recovery from cerebral infarcts. In some embodiments, a composition provided herein is used (e.g., by administering to an individual, such as in need thereof) to alleviate “brain fog” post chemotherapy. In some embodiments, a composition provided herein is used (e.g., by administering to an individual, such as in need thereof) to reduce pulmonary sequelae post long infections regardless of etiology. In some embodiments, a composition provided herein is used (e.g., by administering to an individual, such as in need thereof) to reduce sequelae of autoimmune conditions. In some embodiments, a composition provided herein is used (e.g., by administering to an individual, such as in need thereof) to provide drug levels with potential efficacy as antimicrobials and anti-inflammatory, including reduced ROS and improved T cell function systemically and crossing the blood - brain barrier. In some embodiments, a composition provided herein is used (e.g., by administering to an individual, such as in need thereof) to lyse microbial biofilms, reduce antibiotic resistance, and / or inhibit viral invasion, replication, and / or inflammatory cytokine storm.VAZO-701-WO-PCTOl

[0197] In some embodiments, a composition (or nanoparticle thereof) provided herein comprises Bismuth, Gold, Silver, Platinum, Copper, Magnesium, or other transition or soft metals. In some embodiments, a (metal-containing) nanoparticle provided herein is present in a composition provided herein in a concentration of 5 ug / ml or less, more preferably 2 ug / ml or less, and most preferably 0.2 ug / ml or less.

[0198] In some embodiments, disclosure of a percentage (%) of a component in a composition or nanoparticle includes disclosure a weight (wt.) percentage of the whole of the composition or the nanoparticle. In some instances, the weight percent refers to a weight / weight percentage of the whole. In other instances, the weight percentage refers to a weight / volume percentage of the whole.

[0199] In some embodiments, a composition (or nanoparticle thereof) provided herein comprises one or more of Gly cyrrhizin, Gallic acid, DGG, phenolic acid, or methylene blue. In some embodiments, a composition (or nanoparticle thereof) provided herein comprises 0.5% GA + DGG (deacylated gellan gum) + 0.5% Na-CMC + 0.1% GA2(18 (3 -glycyrrhiitinic acid). In some embodiments, a composition (or nanoparticle thereof) provided herein comprises methylene blue in an amount of 0.02% or less.

[0200] In some embodiments, a composition (or nanoparticle thereof) provided herein comprises a lattice type large surface area (scaffolding). In some embodiments, a composition (or nanoparticle thereof) provided herein comprises a lattice like scaffolding comprising a combination of two or more components selected from the group consisting of poly alpha lysine (alpha PLL), poly epsilon lysine (epsilon PLL), PLGA, pectin, gellen, or other mucoadhesives, mesoporous silicon, graphine oxide (GO), and GOQD. In some embodiments, a composition (or nanoparticle thereof) provided herein comprises a lattice like scaffolding comprising a combinations of PLL, such as PLL-PEG, PLL-mPEG, PLL-cyclodextrin, PLL-hyaluronic acid, PLL-PLGA, and or combinations thereof of three or more excipients; including structures such as PLL-PGE-PLGA; PLL-mPGE-PLGA; PLL-B-HPCD’ PLL-B-HPCD-Hyaluronate / HA / / Mesoporous silicon as examples. In some instances, the lattice adds hydrophilic and hydrophobic molecules; and or hydrophilic and hydrophobic molecules, thereby increasing microbial cellular disruption of largely lipophilic cell membrane surfaces.

[0201] In some embodiments, a composition (or nanoparticle thereof) provided herein comprises both hydrophilic and lipophilic antioxidants. In some embodiments, a lipophilic antioxidant is quercetin, apigenin fisetin, astaxanthin, sea buckthorn oil, or other Log 2.0 or greater antioxidant. In some embodiments, antioxidants are nanoparticles as carbonized nanogels (pyrolysis), laser ablation; or chemical reduction with apply ing organic or inorganic reducing agents including but not limited to sodium citrate, sodium borohydride, amine-borane complexes; chemical stabilizersVAZO-701-WO-PCTOlsuch as polyphenols, phenolic acids such as propyl gallate, caffeic acid, protocatechuic acid, ferulic acid, and vanillic acid, gallic acid among others; and or surfactants such as combinations of SPAN and polysorbates.

[0202] In some embodiments, a composition (or nanoparticle thereof) provided herein comprises cyclodextrins, viscosity agents such as hyaluronic acid, negatively charged moieties such as polyglycerol sulfate.

[0203] In some embodiments, a composition (or nanoparticle thereof) provided herein comprises hydrophilic components, such as glutamate, hydrophilic amino acids, hydroxytyrosol, acetyl cysteine, NAD, NMN, orNMR as examples.

[0204] In some embodiments, a composition provided herein is formulated as a nasal spray, otic drops, pharyngeal spray, sublingual drops, [inhaler, powered inhaler, nebulizer, tablet, gel, suppository or oral capsule or gel. In some instances, blood brain barrier absorption is facilitated, and upper nasal turbinate spray can facilitate BBB absorption.

[0205] In some embodiments, a composition (or nanoparticle thereof) provided herein comprises at least two components selected from the group consisting of a transition metals (e.g., Bismuth, Gold, Silver, Zinc, Copper, Platinum, Cadmium, Nickel), a transition metal oxide (e.g., nanoparticle thereof), or a transitional metal green synthesis (e.g., Phyto Nanoparticles, Nanoemulsions).

[0206] In some embodiments, a composition (or nanoparticle thereof) provided herein is formulated as a Tablet (e.g., Including Slow Release), Gel (e.g., Including Slow Release), Nasal Spray, Nasal Drops, Respiratory Aerosol, Respiratory Nebulizer, Pharyngeal Spray, Suppository, Oral (e g., via slowly degrading protective capsule), Dermatologic (e.g.. Via Cream, Lotion, Or Patch), or Oral shot.

[0207] In some embodiments, a composition (or nanoparticle thereof) provided herein comprises boron, selenium, silicon, germanium, c, antimony, or tellurium.

[0208] In some embodiments, a composition (or nanoparticle thereof) provided herein comprises PEG. In specific embodiments, PEG is from 20 to 2000 repeat units. In some embodiments, the PEG is PEG400.

[0209] In some embodiments, a composition (or nanoparticle thereof) provided herein comprises an antioxidant, such as described herein, in some embodiments, the antioxidant comprises a vitamin E (e.g., Trolox).

[0210] In some embodiments, a composition (or nanoparticle thereof) provided herein comprises a surfactant (e.g., non-ionic surfactant). In some embodiments, the surfactant is Span20, Span 80, Polysorbates, Poloxamers, Sorbitans, S teary I Alcohols, TPGS Or Derivatives, Peg-40 Hydrogenated Castor Oil. Decyl Glucoside, Decyllh;Ivpostearate, IGEPAL CA- PolyglucoseVAZO-701-WO-PCTOlPolyglucose, Glycerol Monostea Polyglycoside, Cetosteearyl AlcoohoL Cetyll Alcohol, Cocaamide DEA, Cocamide MEA, Decyl Glucoside, Decyl Poly glucose, Glycerol Monostearate, IGEPAL CA-630, Isoceteth-20, Lauryl Glucoside, Maltoside, Monolaurin, Myucosubitilin, Ethoxylate, Nonidet P-40, Nonoxynol-9, Nonoxynols, NP-40, Ocataethylene Glycol, Monododecyl Ether, N-Octyl Beta-D-Thioglucopryanoside, Octyl Glucoside, Oleyel Alcohol, Plentaethyhlene Glycol Monododecyl Ether, Polidocanol, Polyethoxylated Tallow Amine, Polyethylene Glycol, Cetyl Ethers, Surfactin, or Tritons.

[0211] In some embodiments, a nanoparticle (e.g., nanoemulsion or nanocapsule nanoparticle) provided herein has a particle size of about 100 nm or less. In some embodiments, a nanoparticle (e.g., nanoemulsion or nanocapsule nanoparticle) provided herein has a particle size of about 50 nm or less. In some embodiments, a nanoparticle (e.g., nanoemulsion or nanocapsule nanoparticle) provided herein has a particle size of about 25 nm or less. In some embodiments, a nanoparticle (e.g., nanoemulsion or nanocapsule nanoparticle) provided herein has a particle size of about 20 nm or less. In some embodiments, a nanoparticle (e.g., nanoemulsion or nanocapsule nanoparticle) provided herein has a particle size of about 15 nm or less.

[0212] In some embodiments, a nanoparticle (e.g., nanoemulsion or nanocapsule nanoparticle) provided herein comprises a transition metal - quercetin nanoemulsion complex. In specific embodiments, the transition metal compises zinc, copper, or silver.

[0213] In some embodiments, a nanoparticle (e g., nanoemulsion or nanocapsule nanoparticle) provided herein comprises a transition metal - pyrithione nano emulsion complex. In specific embodiments, Au, Ag, Zn, Cu, Platinum, or Titanium.

[0214] In some embodiments, a nanoparticle (e.g.. nanoemulsion or nanocapsule nanoparticle) provided herein is prepared using high frequency ultrasound mixing, such as in the presence of a nonionic surfactant. In specific embodiment, the nonionic surfactant comprises a polysorbate or a span.Examples

[0215] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. It is not intended that the invention be limited by the specific examples provided within the specification. While the invention has been described with reference to the aforementioned specification, the descriptions and illustrations of the embodiments herein are not meant to be construed in a limiting sense. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. Furthermore, it shall be understood that all aspects of the invention are not limited to the specific depictions,VAZO-701-WO-PCTOlconfigurations or relative proportions set forth herein which depend upon a variety of conditions and variables. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is therefore contemplated that the invention shall also cover any such alternatives, modifications, variations, or equivalents. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.Example 1;

[0216] An exemplary nasal spray composition provided herein can comprise:1. Au-EGCG NP (5-20 nM preferred)2. Bi-HPCD lowest dose of examples3. CNGQUERsqur (Quercetin NP): Carbonized nanogel (150-170 nm preferred)4. Astaxanthin NLC (NP)5. Poly - a - Lysine (PLL)-PEG-PLGA (with low to high PEG or both) 6. L-theanine7. PEG-MW low to high or both8. EDTA9. BAK10. PS8011. Mannitol12. Hyaluronate (HPMC) or other)

[0217] The nasal spray may optionally use twin fluid atomizers. It can be designed to create droplets of 10-20 um, at a viscosity' of 75-300 cps 0 shear. In vitro laboratory testing can be used to evaluate inhibition over a host of viruses, their strains, and mutations. Clinical testing can be used to evaluate a host viral substrate with high community incidence, such as common colds via rhinoviruses or adenoviruses, seasonal influenza, enteroviruses (GI viral infections).Example 2;

[0218] An exemplary' composition provided herein can comprise:1. Au-EGCG NP (5-20 nM preferred)2. Bi-HPCD increased dose vs #13. CNGQUERsqur (Quercetin NP): (CNGsQur)Carbonized nanogel (150-170 nm preferred)4. Astaxanthin NLC (NP)5. Poly - a - Lysine (PLL)-PEG-PLGA 0 (with low to high PEG or both:MW’s varied vs 1 above)6. L-theanine7. PEG-MW low to high or both (disable PEG #5 immunogenicity function; varied vs 1 above)8. EDTAVAZO-701-WO-PCTOl9. BAK10. PS8011. Mannitol12. Hyaluronate (possibly HPMC) or other)

[0219] Addition of PLL entities can add a surface area high density' scaffold.Example 3

[0220] An exemplary composition provided herein can comprise:1. Au-EGCG NP ; <= 20 nM preferred2. Bi-HPCD (<=20 nm preferred; < 200 nm acceptable increased dose vs #2 3. QUERsqur (Quercetin NP): (CNGsQur)Carbonized nanogel;<170 nm acceptable4. Astaxanthin NLC (NP): <200 nm preferred5. Poly - a - Lysine (PLL)-PEG-PLGA (with continued MW PEG variations) 6. L-theanine7. PEG-MW low to high or both (disable PEG #5 immunogenicity function) 8. EDTA9. BAK10. PS8011. Mannitol12. HPMC13. Sea Buckthorn Oil NPExample 4

[0221] An exemplary composition provided herein can comprise:1. Ag-EGCG NP (5-20 nM preferred). Here lower dose vs Au2. Bi-HPCD higher dosing vs #3 above3. QUERsqur (Quercetin NP): (CNGsQur)Carbonized nanogel(1 0-170 nm preferred)4. Astaxanthin NLC (NP)5. Poly - a - Lysine (PLL)6. L-theanine7. PEG-4008. EDTA9. BAK10. PS8011. Mannitol12. HPMC13. Astodrimer14. Sea Buckthorn Oil NP15. "GA loaded in-site gelling formulationExample 5

[0222] An exemplary composition (e g., Tablet; Gel Capsule; 2-4 oz Supplement (2) QD or BID) provided herein can comprise:VAZO-701-WO-PCTOli. Zinc glycinate 10 mgii. Quercetin 150 mgiii. EGCGiv. Astaxanthinv. Vitamin Cvi. Beetrootvii. Lithium Orotateviii. Span 20 / 80 nanoemulsion**Optional Mix: High frequency ultrasound, barbell distribution; optimized nanoemulsion 1-50 nMExample 6

[0223] An exemplary composition (e g., Tablet; Gel Capsule; 2-4 oz Supplement (2) QD or BID) provided herein can comprise:i. Zinc glycinate 10 mgii Copper gluconate 1.5 mgiii. Quercetin 150 mgiv. EGCGv. Astaxanthinvi. Vitamin Cvii. Beetrootviii. Lithium Orotateix. Span 20 / 80 nanoemulsion**Optional Mix: High frequency ultrasound, barbell distribution; optimized nanoemulsion 1-50 nMExample 7

[0224] An exemplary composition (e g., Tablet; Gel Capsule; 2-4 oz Supplement (2) QD or BID) provided herein can comprise:i. Zinc glycinate 10 mgii Copper gluconate 1.5 mgiii. Selenium Phyto NP 1-50 ug / mliv. Quercetin 150 mgv. EGCGvi. AstaxanthinVAZO-701-WO-PCTOlvii. Vitamin C, Dviii. Beetrootix. Lithium Orotatex. Span 20 / 80 nanoemulsion**Optional Mix: High frequency ultrasound, barbell distribution: optimized nanoemulsion 1-50 nMExample 8

[0225] An exemplary composition (e g., Tablet; Gel Capsule; 2-4 oz Supplement (2) QD or BID) provided herein can comprise:i. Zinc glycinate 10 mgii Cuprous Oxide (CU2O) gluconateiii. Selenium Phyto NP l-50 ug / mliv. Quercetin 150 mgv. EGCGvi. Astaxanthinvii. Vitamin C, Dviii. Beetrootix. Lithium Orotatex. Span 20 / 80 nanoemulsion**Optional Mix: High frequency ultrasound, barbell distribution; optimized nanoemulsion 1-50 nMExample 9

[0226] An exemplary composition (e.g., Tablet; Gel Capsule; 2-4 oz Supplement (2) QD or BID) provided herein can comprise:i. Zinc glycinate 10 mgii Cuprous Oxide (CU2O) Phyto NPiii. Selenium Phyto NP 1-50 ug / mliv. Quercetin 150 mgv. EGCGvi. Astaxanthinvii. Vitamin C, Dviii. Beetrootix. Lithium Orotatex. ApigeninVAZO-701-WO-PCTOlx. Span 20 / 80 nanoemulsion**Optional Mix: High frequency ultrasound, barbell distribution; optimized nanoemulsion 1-50 nMExample 10

[0227] An exemplary composition (e g., Tablet; Gel Capsule; 2-4 oz Supplement (2) QD or BID) provided herein can comprise:i. Zinc glycinate 10 mgii Copper gluconate 1.5 mgiii. Selenium - Baicalin Phyto NP 1-50 ug / mliv. Quercetin 150 mgv. EGCGvi. Astaxanthinvii. Vitamin C, Dviii. Beetrootix. L-Theanine 150 mgx. Lithium Orotate 0.015 mgxi. Apigeninxii. SilibininOptional Mix: High frequency ultrasound, barbell distribution; optimized nanoemulsion 1-50 nM.Example 11

[0228] An exemplary composition (e.g., Nasal Spray, optional UNS long snout adapter 15 ml) provided herein can comprise:i. Zinc glycinate 2.5 mg / ml / Copper gluconate 0.5 mg / mlii. Selenium Phyto NP 1-50 ug / mliv. Quercetin 100 mgv. EGCGvi. Astaxanthinvii. Vitamin C, Dviii. Vitamin E 0.10%:viii. Beetrootix. L-Theanine 150 mgx. Lithium Orotate 0.015 mgVAZO-701-WO-PCTOlxi. Oxymetazoline HCL 0.05%xii. Other: Benzyl Alcohol, Camphor, EDTA, Menthol, Polysorbate 80, Propylene glycol, Sodium Phosphate Dibasic, Sodium Phosphate Monobasic. [Afrin Nasal Spray Severe Congestion]Optional Mix: High frequency ultrasound, barbell distribution; optimized nanoemulsion 1-50 nM.Example 12

[0229] An exemplary composition (e.g., Tablet; Gel Capsule; 2-4 oz Supplement (2) QD or BID) provided herein can comprise:i. Zinc glycinate 10 mgii Copper gluconate 1.5 mgiii. Selenium Phyto NP 1-50 ug / mliv. Quercetin 150 mgv. EGCGvi. Astaxanthinvii. Vitamin Cviii.ix. Beetrootx. Lithium Orotatexi. Apigeninxii. Silibininxiii. Phosphatidyl Serinexiv. Span 20 / 80 nanoemulsion**Optional Mix: High frequency ultrasound, barbell distribution; optimized nanoemulsion 1-Example 13

[0230] An exemplary composition (e.g., Tablet; Gel Capsule; 2-4 oz Supplement (2) QD or BID) provided herein can comprise:i. Zinc glycinate 10 mgii Copper gluconate 1.5 mgiii. Selenium Phyto NP 1-50 ug / mliv. Quercetin 150 mgv. EGCGVAZO-701-WO-PCTOlvi. Astaxanthinvii. Vitamin Cviii. Beetrootix. Lithium Orotate (< 0.3 mg)x. Apigeninxi. Silibininxii. Luteolinxii. Zeaxanthinex. Span 20 / 80 nanoemulsion**Optional Mix: High frequency ultrasound, barbell distribution; optimized nanoemulsion 1-50 nMExample 14

[0231] This example was used to synthesize liposomes using DOPE:CHEMS:DSPC:Cholesterol at a 4:2:2:2 ratio, evaluate their size and stability over time, and assess the effects of lyophilization, with and without trehalose as a stabilizing excipient. The study evaluates the encapsulation of silver nanoparticles (AgNPs) into liposomes to generate hybrid nanostructures with enhanced functional properties.

[0232] l,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), cholesteryl-hemisuccinate (CHEMS), l,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), Cholesterol, methanol, sodium phosphate dibasic, sodium phosphate monobasic, tannic acid, sodium citrate, 0.1 N silver nitrate solution, 4-(2-Hydroxyethyl) piperazine- 1 -ethanesulfonic acid (HEPES) were used to synthesize liposomes. 20 mg of lipids were dissolved in 2 mL chloroform: methanol (3:1 v / v) with the molar ratio DOPE:CHEMS: DSPC: Cholesterol = 4:2:2:2.

[0233] A thin lipid film was formed using a rotary evaporator under vacuum. Temperature was set to 45°C and the pressure was 100 mBar. 2.5 mL, 0. IM phosphate buffer was added at pH 7.4 and sonicated using a water bath sonicator for 5 minutes at 45 °C. The film was incubated at 45 °C for 40 min with stirring. The product was sonicated for 8 minutes using a sonic dismembrator (2 s on, 1 s off, amplitude 30%). The sample was centrifuged at 20,000 rpm for 10 minutes. The supernatant was sonicated for 4 minutes using a sonic dismembrator (2 s on, 1 s off, amplitude 30%). After each minute, sonication was paused for 1 minute. The sonicated liposome solution was used. Approximately 4 nm (by volume) silver nanoparticles (AgNPs) were encapsulated into liposomes during hydration and sonication steps. Solution was lyophilized.

[0234] Particle size and morphology of AgNP-loaded and unloaded liposomes were characterized. Particle size and zeta potential were measured for samples stored at roomVAZO-701-WO-PCTOltemperature and 4 °C on Day 0 (day of synthesis). Day 3, and Day 7 using a Malvern Zetasizer Nano-ZS.

[0235] Dynamic Light Scattering (DLS) measurements were performed immediately after synthesis (Day 0), and after storage at 4 °C for 3 and 7 days. On Day 0, replicate averages ranged from 101.7 nm to 137.4 nm, with narrow standard deviations (3.5-5.6 nm), indicating uniform particle distribution. Minor secondary peaks (-28-29 nm) were observed in some runs. On Day 3, average size increased to 108.3 nm-143.4 nm, with slightly higher variability. Occasional small peaks (-30 nm) persisted, but intensity was low (<2%), confirming that the main population remained in the 100-150 nm range. On Day 7. further size increase observed: 110.3 nm-151.8 nm. Repeated size measurements on Days 3 and 7 indicated a gradual increase in particle size over 1 week. Zeta potential was measured on Day 0 and Day 7. The Zeta potential on Day 0 was -30.05 mV (SD 0.6). The Zeta potential on Day 7 was -30.55 mV (SD 1.2). A minimal change over 7 days was observed, suggesting that the surface charge remained stable.

[0236] Lyophilization was performed under two conditions: (a) no additive (b) with 5% w / v trehalose. With no trehalose, particle size increased averaging 250-300 nm, with peaks exceeding 500-600 nm in some runs. Multiple peaks appeared, suggesting severe aggregation and possible vesicle fusion. Standard deviations were high, suggesting heterogeneity. With 5% w / v trehalose, the average particle size was 250-300 nm, similar to that of the samples without trehalose. This suggests addition of trehalose does not affect the particle size of the lyophilized liposomes. Liposomes freeze-dried without additives showed extensive size increases and aggregation after reconstitution, while liposomes freeze-dried with 5% w / v trehalose maintained better size integrity, suggesting trehalose’s effectiveness as a cryoprotectant.

[0237] After AgNP inclusion, particle size of 3 AgNP-loaded liposome replicates were measured. Liposomes retained a consistent size profile after AgNP inclusion. Addition of trehalose does not affect the particle size of the lyophilized liposomes

[0238] SEM was used to visualize structural differences caused by AgNP incorporation. SEM imaging showed morphological differences between liposomes without AgNP (FIG. 1A and IB) and AgNP-loaded liposome (FIG. 1C and ID), with AgNP formulations exhibiting more structured, rigid, and layered morphologies.Example 14

[0239] This example was used to synthesize glycyrrhizic acid nanoparticles (GANP) using a hydrothermal, alkaline-pH method and analyzed for particle size, zeta potential, and stability at room temperature and 4 °C over 10 days. Additionally, SEM imaging was performed to evaluate the morphological characteristics of GANP with and without trehalose as a stabilizing excipient.VAZO-701-WO-PCTOl

[0240] Glycyrrhizic acid, 25 mL Teflon coated hydrothermal reactor, 6-8 kDa MWCO dialysis bag, and 18.2 MQ-cm di-water were used. Specifically, glycyrrhizic acid (10 mg / mL): 50 mg was dissolved in 5 mL deionized water and adjusted to pH 9.0 using 1 M NaOH. The solution was incubated for 6 hours at 185 °C in a hydrothermal reactor. After incubation, the reactor was cooled using an ice bath. The product was sonicated for 4 minutes using a sonic dismembrator (2 s on, 1 s off, amplitude 30%). After each minute, sonication was paused for 1 minute. The sample was centrifuged at 20,000 rpm for 10 minutes. The supernatant was collected, and small precipitates were removed using a dialysis bag (6-8 kDa MWCO) for 12 hours. Water was changed after the first 2 hours, after 12 hours, and again after 2 additional hours. The dialyzed sample was centrifuged again at 20,000 rpm for 10 minutes. The supernatant was collected, sonicated for 4 minutes, and centrifuged at 20,000 rpm for 10 minutes. The desired GANP was in the supernatant.

[0241] Particle size and zeta potential of GANP were measured using a Malvern Zetasizer Nano-ZS. Particle size and zeta potential were measured for samples stored at room temperature and 4 °C on Day 0 (day of synthesis), Day 2, Day 5, and Day 10.

[0242] A 300 pL aliquot of each sample was lyophilized using an SP VirTis Advantage Pro freeze dry er. Two GANP samples were lyophilized, with 100 pL of 5% w / v (50 mg / mL) trehalose and without excipient. On Day 0, particle size (intensity) of peak 1 (12-20% distribution) w as observed at -25-35 nm and peak 2 (dominant) was observed at -165-205 run. Particle size (volume) of peak (dominant population) was observed at -28-33 nm. The average zeta potential was approximately -33 mV. Initial GNAP displayed a bimodal size distribution, with primary7particles -30 nm and secondary7assemblies -180 nm. On Day 2. at room temperature, particle size (intensity) increased slightly. Peak Iwas observed at -141-178 nm and peak 2 was observed at -200-260 nm. Particle size (volume) of Peak 1 was observed at -101-140 nm and peak 2 was observed at -262-308 nm. The Average Zeta potential was -23.7 mV. At 4 °C, particle size (intensity) of peak 1 was observed at -139-178 nm and peak 2 was observed at -202-220 nm. Particle size (volume) of peak 1 w as observed at -128-168 nm and peak 2 was -190-220 nm. The Average Zeta potential was -34.1 mV. On Day 5, at room temperature, particle size (intensity) drifted higher. Peaks were observed at 160-280 nm, some >300 nm and some -17-35 nm. Particle size (volume) showed a similar trend: Peaks were observed at 136-155 nm, some >300 nm and some -16-29 nm. The Average Zeta potential was -16 mV. At 4 °C, there w as smaller overall shift particle size (intensity): Peak were observed at 150-220 nm with some small (-15-30 nm) peaks remain for both intensity and volume-based DLS measurements, suggesting 4 °C storage inhibits aggregation. The Average Zeta potential was -35.2 mV. On Day 10, at room temperature, dominant peak shifted to 260-350 nm for both intensity and volume-based distributions. More homogeneous distribution was observed. Average zeta potential was -18.8 mV. At 4 °C, particle size (intensity) of peaks wereVAZO-701-WO-PCTOlobserved at -108-198 nm, some >200 nm and some -18-29 nm. Particle size (volume) showed a similar trend: peaks observed at -130-161 nm, some >200 nm and some -16-29 nm. The Average Zeta potential was -36.1 mV. The overall zeta potential measurements suggested that samples stored at 4 °C exhibit greater stability. Stability studies indicated that 4 °C storage substantially slows aggregation, whereas room-temperature storage leads to progressive size increases by Day 10.

[0243] SEM images of the lyophilized samples were obtained using a Phenom Pro X SEM. GNAP without trehalose (FIG.2A) exhibits collapsed, fused structures. GNAP with trehalose (FIG. 2B) retains more spherical, discrete morphologies.

[0244] These results suggest trehalose enhance GNAP stability during drying and storage.Example 15

[0245] This example was used to synthesize glycine-stabilized EGCG nanoparticles (EGCG-NP), load them with silver (EGG-AgNP), and compare their particle size, zeta potential, stability, lyophilization behavior, and morphology.

[0246] Epigallocatechin gallate, formaldehyde solution, glycine, 0.1 M silver nitrate, trehalose, tween 80, and 18.2 MQ-cm di-water were used. EGCG (91.5 mg) and formaldehyde solution (30 pL) were dissolved in 20 mL of deionized water, stirring vigorously at 30°C. Glycine (15 mg) was added to the solution and continue stirring for 2 hours. The mixture was centrifuged at 10,000 rpm for 10 minutes. 10 mL water was added, the pellet was resuspended and the mixture was centrifuged at 10000 rpm for 10 min. This step was repeated twice. 1 mL water was added, the pellet was resuspended, and the solution was transferred into a 1 mL Eppendorf tube and centrifuged at 10000 rpm for 10 min. The pellet was resuspend in 5 mL of deionized water. The prepared nanoparticles was restored at 4°C until further use. 4 mg / mL Gly NPs solution was mixed with 0.1 M silver nitrate (total volume 1 mL) while stirring vigorously at 25 °C. The mixture was sonicated for 20 minutes to ensure fully incorporation of the silver nanoparticles (color change from milky white to yellow was used to indicate successful AgNP loading). The solution was centrifuged at 10000 rpm for 10 minutes. Supernatant was removed, 1 mL of water added, the pellet w as resuspended, and the mixture w as centrifuged at 10000 rpm for 10 minutes. This step w as repeated three times. The pellet was resuspend in 1 mL of water and store at 4 °C.

[0247] Particle size and zeta potential measurements were made using a Malvern Zetasizer Nano-ZS for both EGCG-NP and EGCG-AgNP. Particle size and zeta potential were measured for samples stored at room temperature and 4 °C on Day 0 (day of synthesis), Day 3, and Day 7.

[0248] A 300 pL aliquot of each sample was lyophilized using an SP VirTis Advantage Pro freeze dryer. The following samples were lyophilized, with and without excipient:VAZO-701-WO-PCTOl• Sample #1: 300 pL EGCG-NP without an excipient• Sample #2: 300 pL EGCG-AgNP without an excipient• Sample #3: 300 pL EGCG-NP with 100 pL of 5% w / v (50 mg / mL) trehalose• Sample #4: 300 pL EGCG-NP with 100 pL of 5% w / v (50 mg / mL) trehalose and 0.1% w / v tween 80• Sample #5: 300 pL EGCG-AgNP with 100 pL of 5% w / v (50 mg / mL) trehalose• Sample #6: 300 pL EGCG-AgNP with 100 pL of 5% w / v (50 mg / mL) trehalose and 0.1% w / v tween 80

[0249] EGCG nanoparticles were synthesized using glycine as a stabilizer and had a yield of -36 wt%. Final Gly-NP concentration was 16.7 mg / mL. The silver-loaded EGCG-NP exhibited a yellow color shift, indicating silver incorporation. The yield increased to -72 wt% after silver loading. Final concentration after silver incorporation was -12.15 mg / mL. Particle size and zeta potential measurements for EGCG-NP at a concentration of 4.1 mg / mL were measured in 3 replicates: Replicate 1: Avg size -606 nm (intensity), -660 nm (volume); Replicate 2: Avg size -563 nm (intensity), -606 nm (volume); Replicate 3: Avg size -539 nm (intensity), -580 nm (volume). Size decreases slightly across replicates; variability noted. The average zeta potential was approximately -34.2 mV. Particle size and zeta potential measurements for EGCG-AgNP at a concentration of 8.0 mg / mL were measured. Particle sizes ranged from -635 nm to -1529 nm depending on peaks and replicates. Volume-based averages for silver-loaded particles was observed at -1436 nm (with variability). Average zeta potential was approximately -44.3 mV. On Day 0, Day 3, and Day 7, particle sizes ranged from -300 nm to -855 nm depending on peaks and replicates. Volume-based averages for silver-loaded particles -750 nm (with variability ).

[0250] Particle size lyophilized EGCG -NP- reconstituted in water was measured under two conditions. EGCG -NP in 5% trehalose sizes ranged -489-641 nm across replicates with variability observed. EGCG -NP in 5% trehalose + 0.1% Tween 80 sizes ranged -567-760 nm. higher variability and larger aggregates was observed compared to trehalose-only. EGCG -NP particle size increased after lyophilization, especially with the Tween 80 additive.

[0251] Particle size lyophilized lyophilized EGCG -AgNP-reconstituted in water was measured under two conditions. EGCG -AgNP in 5% trehalose sizes ranged -875-945 nm (intensity-based) and -965-1031 nm (volume-based). EGCG -AgNP in 5% trehalose + 0.1% Tween 80 peaks at -50-144 nm and -244-1399 nm (multi-peak distributions observed), suggesting aggregation and possible bimodal distribution.

[0252] Both EGCG-NP and EGCG-AgNP showed substantial increases in size after lyophilization. Tween 80 addition led to greater variability and larger aggregates than in trehalose-only samples.VAZO-701-WO-PCTOl

[0253] Silver loading substantially increases yield and may enhance functional properties of the EGCG-NP formulation. Color change and particle size data suggest successful metallization. EGCG-NP synthesis achieved a high yield and a stable particle size (-500-600 nm), with particle size remaining stable at 4 °C across Days 0, 3, and 7. Silver loading substantially increased particle size (>1 pm). Zeta potential measurements indicate changes in surface charge upon silver incorporation.

[0254] SEM images were obtained using a Phenom Pro X scanning electron microscope. Freeze-drying and SEM imaging (FIG. 3A-3J) showed structural integrity and differences in morphology.Example 16

[0255] This example was used to synthesize AgNPs, coating them with mesoporous silica, and evaluating their size distribution, morphology, and colloidal stability using DLS, zeta potential measurements, and qualitative observations.

[0256] Tannic acid, sodium citrate, 0.1 M silver nitrate solution, cetyltrimethylammonium (CTAC), sodium hydroxide, tetraethyl orthosilicate (TEOS), ethanol, and 18.2 MQ-cm di-water were used. 100 mL of an aqueous solution containing tannic acid (TA) 0.1 mM and sodium citrate (SC) 5 mM was placed in a double-neck round-bottom flask adapted with a condenser. The solution was heated with vigorous stirring, and after boiling for 15 minutes, 2 mL of AgNO3 (25 mM) was quickly injected, causing an immediate change to a yellow color. The reaction was considered complete after boiling for 45 min; then, the solution was cooled under stirring at room temperature. A total of 100 mL of this colloidal solution was purified through centrifugation (8500 rpm x 30 min), to remove the TA and SC excess, and redispersed in 90 mL of SC 2.2 mM. 97.3mL of water and 1920 pL of CTAC 50mM were placed in a round-bottom flask. 20 mL of NPs in NaOH 2 mM (concentration -5.8 * lOllNPs / mL Ag) was added to the reaction under vigorous magnetic stirring. After 5 min. 800 pL of NaOH 0.1M was injected, and the solution was moderately stirred for 24 h. Afterwards, 4 mL of EtOH containing TEOS was sequentially dripped (800 pL each 10 min) under stirring (small Ag or Au NPs were coated using 80 pL of TEOS was used). The bottom flask was capped, and moderate stirring was maintained for 24 h at room temperature. Finally, the MPS-AgNP were purified with 3 centrifugation cycles (rpm range 9000-6500 x 30 min) in EtOH for microscopy analysis. The colloid solutions were stored in EtOH at 4 °C for further use.

[0257] Two AgNP concentrations were tested for coating: (a) 5.8 x 1011NPs / mL and (b) 4.8 x 1013NPs / mL. The nanoparticle concentration was calculated based on quantitative metal reductionl. using Ag density (10.5 g / cm3), atomic mass (107.9 g / mol), and DLS-derived particle diameter (3.6 nm). The estimated total nanoparticle count was 2.2 x 1016particles, corresponding to a final concentration of 4.8 x 1013NPs / mL. Low AgNP concentration (5.8 x 1011NPs / mL)VAZO-701-WO-PCTOlshowed no visible pellet after centrifugation High concentration (4.83 x 1013NPs / rnL) showed pellet formed, but yield remained low.

[0258] Dynamic Light Scattering (DLS) were used to measure particle size AgNP. Two peaks were observed. Peak l(low intensity) was observed at ~3-5 nm. Peak 2(dominant intensity) was observed at -43-45 nm. Peak 1 of average size (by intensity) was observed at -4 nm. Peak 2 of average size (by intensity) was observed at -44 nm. Peak 1 of volume-based averages was observed at -3.3-3.9 nm. Peak 2 of volume-based averages was -29.5-30 nm. Standard deviations ranged from 0.7-1.1 nm for Peak 1 and -15-16 nm for Peak 2. AgNPs show a bimodal size distribution, with most around 30 nm and a smaller group near 3.6 nm (by volume).

[0259] For MPS-AgNPs, the reaction color was brown-green instead of yellow, which may suggest an incomplete reduction. AgNP size was -50-60 nm (intensity-based) and -35-40 nm (volume-based). Pellets were formed in silica coating trials with lower AgNP concentrations (6 x 1011and 20 x io11NPs / mL) with low yield. Particle size after coating was observed at 177-173 nm and 328-395 nm, depending on concentration. Approximate zeta potential was observed at -32 mV.

[0260] High AgNP concentration maybe important for obtaining successful mesoporous silica-coated nanoparticles. Although DLS confirmed a clear size increase after coating, the overall reaction yield was low at lower AgNP concentrations. The coated particles exhibited moderately negative zeta potentials ( — 32 mV), indicating acceptable colloidal stability.Example 17

[0261] This example was used to synthesize a diblock copolymer using a 0.66 molar ratio of L-lactide to PEtOz, following a modified and optimized procedure. The synthesized copolymer was then formulated into micelles. The resulting nanoparticles were characterized and assessed for short-term stability and morphology using dynamic light scattering (DLS) and scanning electron microscopy (SEM).

[0262] 2-ethyl-2-oxazoline, methyl p-toluenesulfonate, acetonitrile, methanol, potassium hydroxide, dry chlorobenzene, diethyl ether, trehalose, tetrahydrofuran, Treahalose. and 18.2 MQ-cm di-water were used. A solution of 2-ethyl-2-oxazoline (30.00 g, 605 mmol) and methyl p-toluenesulfonate (1.25 g, 12 mmol) in acetonitrile (100 mL) was stirred at reflux for 30 hours under nitrogen. The solution temperature was maintained around 120 °C during the reflux. The solution temperature was let to cool to room temperature. 100 mL of 0.1 N methanolic KOH were added to the solution. The polymer was filtered through silica gel under vacuum. Acetonitrile was used to prepare the silica gel slurry. Approximately 60% v / v of the filtered acetonitrile was removed by rotary evaporation. The product, PEtOz-OH, was isolated by precipitation into ice-cold diethyl ether and then vacuum dry before use. 2.00 g of PEtOz-OH was heated in 15 mL of dry chlorobenzene under reflux using a Dean-Stark apparatus. 10 mL of chlorobenzene wasVAZO-701-WO-PCTOlevaporated and the Dean-Stark apparatus was replaced with a condenser. L-lactide (1.02 g, 7 mmol) was added under nitrogen. The reflux temperature was increased and stannous octoate (4 mg) was added under nitrogen. The reaction was maintained for 30 hours. The copolymer was isolated into ice-cold diethyl ether. To prepare the micellar solutions, deionized water (10 mL) was added dropwise to a gently stirred THF solution (5 mL) of the block copolymer (500 mg). The THF was removed using a rotary evaporator at 30 °C for 2 hours. Micellar solution was passed through a 0.45 pm filter The product was sonicated for 6 minutes using a sonic dismembrator (2 s on, 1 s off, amplitude 30%). After each minute, sonication was paused for 1 minute. The sample was centrifuged at 20,000 rpm for 10 minutes. 2.0 g of PEtOz-OH may yield approximately 1.5-1.8 g of the final copolymer powder. This corresponds to an overall yield of about 75-90%, depending on reaction efficiency and purification losses.

[0263] Particle size of the diblock copolymer was measured using a Malvern Zetasizer Nano-ZS. Particle sizes were measured for micelle samples. The micellar solution was lyophilized, and the lyophilized particles were reconstituted in water, after which particle size was also measured. Particle sizes were measured for samples stored at 4 °C on Day 0 (day of synthesis), Day 3, and Day 7.

[0264] Initial particle size measurements of the filtered copolymer (prior to sonication and centrifugation), with replicate measurements on Day 0, ranged from -870 to -1050 nm. Over the following five days, particle sizes fluctuated substantially (-730 nm to >1000 nm), suggesting instability or continued aggregation without further processing. Sonication substantially improved micelle uniformity. 4 min sonication produced a dominant population around 270-316 nm, though some very large aggregates (>5000 nm) remained. 6 min sonication yielded a much smaller primary size distribution (-30-40 nm and -120-180 nm) with only minor aggregated species (-1300 nm). Subsequent centrifugation removed residual large aggregates, resulting in average particle sizes of -56 nm (intensity) and -35 nm (volume). These smaller micelles remained stable, maintaining sizes between -55-66 nm on Day 3 and -57-61 nm on Day 7, indicating good shortterm stability after processing.

[0265] A 300 pL aliquot of each sample was lyophilized using an SP VirTis Advantage Pro freeze dryer. Two copolymer samples were lyophilized, with 100 pL of 5% w / v (50 mg / mL) trehalose and without excipient. Without trehalose, reconstituted micelles remained small (-40 nm) but occasionally showed large secondary’ peaks (>1400 nm). With 5% trehalose, the main particle size increased slightly (-43-52 nm), and secondary peaks (>500 nm) persisted but became less pronounced.

[0266] SEM images of the lyophilized samples were obtained using a Phenom Pro X SEM.Lyophilized samples without trehalose (FIG.4A and 4B) displayed irregular particle morphology,VAZO-701-WO-PCTOlwith noticeable aggregated clusters. Samples containing trehalose (FIG. 4C and 4D) were more uniform, but still exhibited some degree of clustering.

[0267] In summary7, initial micelles are very7large (>800 nm) and unstable. Sonication and centrifugation are important for reducing sizes to -30-60 nm and improving uniformity. Lyophilization introduces variability, and trehalose acts as a partial stabilizer. Processed micelles demonstrate good stability7over at least 7 days, maintaining consistent particle sizes around 55-60 nm.

Claims

VAZO-701-WO-PCTOlCLAIMS WHAT IS CLAIMED IS:

1. A composition comprising,a) a first nanoparticle comprising a transition metal;b) a mucoadhesive; andc) an optional antioxidant.

2. The composition of claim 1, wherein the transition metal is gold, silver, zinc, or an oxide thereof.

3. The composition of any one of the preceding claims, wherein the first nanoparticle further comprises a soft metal.

4. The composition of claim 3, wherein the soft metal is bismuth.

5. The composition of any one of the preceding claims, wherein the first nanoparticle is a phyto nanoparticle.

6. The composition of any one of the preceding claims, wherein the composition comprises the first nanoparticle in a concentration of about 0.001 mg / mL to about 1 mg / mL.

7. The composition of any one of the preceding claims, wherein the composition further comprises a second nanoparticle that is different from the first nanoparticle.

8. The composition of claim 7, wherein the second nanoparticle comprises bismuth.

9. The composition of any one of the preceding claims, further comprising epigallocatechin gallate (EGCG), quercetin, quercetin selenium, carbonized nanogel quercetin selenium, selenium, a seleno-organic compound, or a combination thereof.

10. The composition of any one of the preceding claims, wherein the first nanoparticle has an average size of about 40 nm or less.

11. The composition of any one of the preceding claims, wherein the first nanoparticle has an average size of 0.1 nm to about 40 nm.

12. The composition of any one of the preceding claims, wherein the first nanoparticle has an average size of about 20 nm or less.

13. The composition of any one of the preceding claims, wherein the first nanoparticle has an average size of 1 nm to about 20 nm.VAZO-701-WO-PCTOl14. The composition of any one of the preceding claims, wherein the composition further comprises a polyphenol.

15. The composition of any one of the preceding claims, wherein the first or second nanoparticle further comprises a polyphenol.

16. The composition of any one of the preceding claims, w herein the mucoadhesive comprises poly a- lysine (PLL), pectin, gellin, PEG, PVA, PVP, poly acrylic acid, poly (hydroxy ethyl methacrylate), chitosan, chitosan-chondroitin sulfate, hydroxyl ethyl cellulose (HEC), astodrimer sodium, MAEMA. PVA, PVP, poly(acrylic acid) (PAA). poly(methacrylic acid) (PMAA), PLL - PEG - PLGA, hyaluronate, hyaluronic acid, or a combination thereof.

17. The composition of any one of the preceding claims, w herein the mucoadhesive comprises PLL - PEG - PLGA.

18. The composition of any one of the preceding claims, wherein the composition comprises the antioxidant.

19. The composition of any one of the preceding claims, wherein the antioxidant is a polyphenol.

20. The composition of any one of the preceding claims, wherein the antioxidant is a phytopolyphenol.

21. The composition of any one of the preceding claims, w herein the antioxidant comprises quercetin, curcumin, carrageenan, or a combination thereof.

22. The composition of any one of the preceding claims, wherein the antioxidant comprises EGCG, GCG, hydroxytyrosol, selenium, glutathione, lithium orotate, beet root, NAD / NMR / NMN, L-theanine, vitamin C, quercetin, quercetagetin, fisetin, apigenin, baicalein, myricetin, an alpha tocopherol, an omega 3 fatty acid, olive oil, lutein, astaxanthin, or a combination thereof.

23. The composition of any one of the preceding claims, further comprising mesoporous silicon.

24. The composition of any one of the preceding claims, further comprising graphene oxide.

25. The composition of any one of the preceding claims, further comprising a compound represented by the following structure:PLL-X -YVAZO-701-WO-PCTOlwherein,X comprises PEG, MPEG, HPGCD, hyaluronate, hyaluronic acid, an amino acid (e.g., lysine, arginine, or histidine), or a peptide (e.g., comprising lysine, arginine, and / or histidine), andY comprises Ga+, Ga+DGG+Hyaluronic acid, or CMC-HPMC.

26. A composition comprising,a) a first nanoparticle comprising a metal and epigallocatechin gallate (EGCG); b) a second nanoparticle comprising quercetin; andc) a third nanoparticle comprising astaxanthin.

27. The composition of claim 26, wherein the metal of the first nanoparticle is gold.

28. The composition of claim 26, wherein the metal of the first nanoparticle is bismuth.

29. The composition of any one of the preceding claims, wherein the first nanoparticle is present in the composition of about 1 nM to about 100 nM.

30. The composition of any one of the preceding claims, wherein the first nanoparticle is present in a composition of about 5 nM to about 20 nM.

31. The composition of any one of the preceding claims, wherein the first nanoparticle comprises silver and the concentration of the first nanoparticle present in the composition is about 0.002 mg / mL or less.

32. The composition of any one of the preceding claims, wherein the first nanoparticle comprises gold and the concentration of the first nanoparticle present in the composition is about 0.2 mg / mL or less.

33. The composition of any one of the preceding claims, further comprising a cyclodextrin.

34. The composition of claim 33, wherein the cyclodextrin is a metal cyclodextrin.

35. The composition of either claim 33 or 34, wherein the cyclodextrin is hydroxypropyl cyclodextrin.

36. The composition of any one of the preceding claims, wherein the second nanoparticle comprises a nanogel.

37. The composition of claim 36, wherein the nanogel is a carbonized nanogel.

38. The composition of any one of the preceding claims, wherein the second nanoparticle has an average size of about 100 nm to about 250 nm.VAZO-701-WO-PCTOl39. The composition of any one of the preceding claims, wherein the composition comprises no more than 0.04 wt. % EGCG (e.g., 0.01 wt. % to 0.04 wt. %).

40. The composition of claim 38, wherein the second nanoparticle has an average size of about 150 nm to about 170 nm.

41. The composition of any one of the preceding claims, wherein the third nanoparticle comprises a lipid carrier.

42. The composition of any one of the preceding claims, wherein the third nanoparticle comprises a nanostructured lipid carrier (NLC).

43. The composition of any one of the preceding claims, wherein the composition comprises a nanostructured lipid carrier (NLC).

44. The composition of either one of claims 42 or 43, wherein the nanostructured lipid carrier has an average (or D99) of about 500 nm or less (e.g.. about 250 nm or less or about 0.05 nm to about 500nm).

45. The composition of any one of the preceding claims, further comprising a chelating agent.

46. The composition of claim 45, wherein the chelating agent is ethylenediaminetetraacetic acid (EDTA).

47. The composition of any one of the preceding claims, further comprising a preservative.

48. The composition of claim 47, wherein the preservative is benzalkonium chloride (BAK).

49. The composition of any one of the preceding claims, further comprising a surfactant.

50. The composition of claim 49, wherein the surfactant is a polysorbate (e.g., polysorbate 80).

51. The composition of any one of the preceding claims, further comprising a tonicity adjusting agent.

52. The composition of claim 51, wherein the tonicity adjusting agent is mannitol.

53. The composition of any one of the preceding claims, further comprising a mucoadhesive.

54. The composition of claim 53, wherein the mucoadhesive is a cellulose or hyaluronate.

55. The composition of claim 53, wherein the mucoadhesive is a hydroxy propylmethyl cellulose (HPMC).

56. The composition of any one of the preceding claims, further comprising a lubricant or moisturizer.VAZO-701-WO-PCTOl57. The composition of claim 56, wherein the lubricant or moisturizer is a polyethylene glycol (PEG).

58. The composition of any one of the preceding claims, further comprising poly-L-lysine- poly ethylene glycol-poly(lactic-co-gly colic acid) (PLL-PEG-PLGA).

59. The composition of any one of the preceding claims, further comprising an antioxidant.

60. The composition of claim 56, wherein the antioxidant comprises L-theanine.

61. The composition of any one of the preceding claims, wherein the nasal spray has a viscosity of about 50 centipoise (cP) to about 500 cP (e.g., at 0 shear).

62. The composition of any one of the preceding claims, wherein the nasal spray has a viscosity of about 70 centipoise (cP) to about 3300 cP (e.g., at 0 shear).

63. The composition of any one of the preceding claims, further comprising water.

64. The composition of any one of the preceding claims, wherein the nasal spray is an aqueous formulation and the first nanoparticle is suspended in the aqueous formulation.

65. The composition of claim 64, wherein the second nanoparticle is suspended in the aqueous formulation.

66. The composition of either claim 64 or 65, wherein the third nanoparticle is suspended in the aqueous formulation.

67. The composition of any one of the preceding claims, further comprising hyaluronic acid, pectin, gellen, glycyrrhetinic acid, gallic acid, phenolic acid, methylene blue (e.g., 0.02 wt % or less), d-glutamyl-lysine (DGG). EGCG, a polyphenol. CMC, BAK, polyglycerol SOV4, glutamate, astaxanthin, poly glycerol sulfate, or a combination thereof.

68. The composition of any one of the preceding claims, further comprising quercetin, beetroot, astaxanthin lithium orotate, span 20, polysorbate (e.g., polysorbate 80), hyaluronate, hyaluronic acid, apgenin silibinin, L-theanine, zinc glycinate, or a combination thereof.

69. A system comprising the composition of any one of the preceding claims, and a device for forming nasal spray droplets of the composition.

70. The system of claim 69, wherein the device is a mist atomizer or a nebulizer.

71. The system of either claim 69 or 70, wherein the device is configured to form nasal spray droplets having a droplet size of about 10 um to 20 um.VAZO-701-WO-PCTOl72. A method of inhibiting viral proliferation by contacting a virus with the composition of any one of claims 1-68.

73. A method of inhibiting viral proliferation in an individual, the method comprising:a) providing the system of any one of claims 69-71 ;b) dispensing a nasal spray from the device, such that the composition is administered to the individual intranasally.

74. A method of inhibiting viral infection in an individual, the method comprising:a) providing the system of any one of claims 69-71;b) dispensing a nasal spray from the device, such that the composition is administered to the individual intranasally.

75. The method of any one of claims 72-74, wherein the droplets have an average size of about 1 um to about 100 um.

76. The method of any one of claims 72-74, wherein the droplets have an average size of about 10 um to about 20 um.

77. A method for reducing absorption and / or proliferation of a virus in an individual, the method comprising administering a composition (e.g., nano-formulation) to the individual, the composition (e.g., nano-formulation) comprising a particle and a lipophilic antioxidant.

78. A method for enhancing nanoparticle delivery to an individual, the method comprising administering a composition (e.g.. nano-formulation) to the individual, the composition (e.g., nano-formulation) comprising a nanoparticle and a lipophilic antioxidant.

79. A method for treating (e.g., prophylactic treatment) a viral infection in an individual, the method comprising administering a composition (e.g., nano-formulation) to the individual, the composition (e.g., nano-formulation) comprising a particle and a lipophilic antioxidant.

80. The method of any one of the preceding claims, wherein the composition (e.g., nanoformulation) further comprises a mucoadhesive.

81. The method of any one of the preceding claims, wherein when the composition (e.g., nanoformulation) is administered (e g., nasally, buccally, sublingually, pulmonary, ortopically) to the individual, enhanced nanoparticle delivery is achieved (e.g., relative to a formulation lacking a lipid antioxidant and / or mucoadhesive).VAZO-701-WO-PCTOl82. The method of any one of the preceding claims, wherein when the composition (e.g., nanoformulation) is administered (e.g., nasally, buccally, sublingually, pulmonary, ortopically) to the individual, reduced absorption and / or proliferation of a virus is achieved (e.g., relative to a formulation lacking a lipid antioxidant and / or mucoadhesive).

83. The method of any one of the preceding claims, wherein when the composition (e.g., nanoformulation) is administered (e.g., nasally, buccally, sublingually, pulmonary, ortopically) to the individual, reduced viral count of a virus (e.g., by reducing absorption and / or proliferation) is achieved (e.g., relative to a formulation lacking a lipid antioxidant and / or mucoadhesive).

84. The method of any one of the preceding claims, wherein administration of the composition (e.g., nano-formulation) to the individual provides anti-viral activity (e.g., against DNA and / or RNA viruses) (e.g.. relative to a composition lacking the lipid antioxidant and / or mucoadhesive).

85. The method of any one of the preceding claims, wherein the formulation comprises a plurality of particles.

86. The method of any one of the preceding claims, wherein the plurality of the particles have an average particle size of about 1 um to 300 um.

87. The method of any one of the preceding claims, wherein the composition comprises the plurality7of the particles formulated as a polymeric capsule.

88. The method of any one of the preceding claims, wherein the polymeric capsules comprise a polymeric coat and a lipophilic core.

89. The method of any one of the preceding claims, wherein the lipophilic core comprises (e.g., stabilized with) one or more surfactants (e.g., a hydrophilic surfactant and a lipophilic surfactant).

90. The method of any one of the preceding claims, wherein the polymeric capsules is prepared using nanoprecipitation.

91. The method of any one of the preceding claims, wherein the polymeric capsules comprise an antioxidant.

92. The method of any one of the preceding claims, wherein the polymeric capsules comprise an antioxidant and PLGA.

93. The method of any one of the preceding claims, wherein the polymeric capsules comprise an antioxidant and oil.VAZO-701-WO-PCTOl94. The method of any one of the preceding claims, wherein the polymeric capsules comprise an antioxidant, polymer (e.g., PLGA), and surfactant.

95. The method of any one of the preceding claims, wherein the polymeric capsules comprise an antioxidant, polymer (e.g., PLGA), oil, and surfactant.

96. The method of any one of the preceding claims, wherein the polymer comprises PLGA.

97. The method of any one of the preceding claims, wherein the polymer comprises an alpha epsilon poly lysine (PLL).

98. The method of any one of the preceding claims, wherein the antioxidant comprises a lipophilic antioxidant.

99. The method of any one of the preceding claims, wherein the antioxidant comprises a curcuminoid, a polyphenol, a carotenoid, or a tocopherol.

100. The method of any one of the preceding claims, wherein the antioxidant comprises astaxanthin.

101. The method of any one of the preceding claims, wherein the antioxidant comprises tertbutyl curcumin, demethylated tert-but lated curcumin (lE,6E-l,7-bis(3-tert-butyl-4,5- digydtoxyphenyl)hepta-2,6 / dime-3,5,dione)(DMTC), or demethylated curcumin.

102. The method of any one of the preceding claims, wherein the plurality of particles comprises folic acid modified albumin particles.

103. The method of any one of the preceding claims, wherein the polymeric capsules comprise chitosan lactate and lactobionic acid (e.g., for use in the targeted treatment of hepatic (liver) pathogens).

104. The method of any one of the preceding claims, wherein the virus is hepatitis.

105. The method of any one of the preceding claims, wherein the virus is HEP A-E, CMV, adenovirus, human herpes virus 6, varicella-zoster, or EBV.

106. The method of any one of the preceding claims, wherein the plurality of particles comprises liposomes.

107. A composition (e.g., nano-formulation) comprising a plurality of particles and a lipophilic antioxidant (e.g., wherein the lipophilic antioxidant may be incorporated into the plurality of particles or separated therefrom).VAZO-701-WO-PCTOl108. A composition (e.g., nano-formulation) comprising a plurality of liposomes and a lipophilic antioxidant (e.g., wherein the lipophilic antioxidant may be incorporated into the plurality' of liposomes or separated therefrom).

109. The composition of any one of the preceding claims, wherein the plurality of particles or plurality of liposomes comprise the lipophilic antioxidant.

110. The composition of any one of the preceding claims, wherein the plurality of particles or plurality of liposomes release the lipophilic antioxidants under acidic conditions.

111. The composition of any one of the preceding claims, wherein the plurality of particles or plurality of liposomes release the lipophilic antioxidants under acidic conditions found at the tissue sites of infectious sequelae (e.g., providing targeted preferential release at the infectious sequelae).1 12. The composition of any one of the preceding claims, wherein systemic toxicity is reduced (e.g., relative to an otherwise similar formulation, not formulated to comprise the particles and liposomes described herein).

113. The composition of any one of the preceding claims, wherein efficacy (e.g., of neutralizing sites) is improved (e.g., relative to an otherwise similar formulation, not formulated to comprise the particles and liposomes described herein).

114. The composition of any one of the preceding claims, wherein the plurality of particles or plurality of liposomes comprise a phospholipid, a cholesterol and a pH sensitive excipient.

115. The composition of any one of the preceding claims, wherein the plurality of particles or plurality' of liposomes comprise a pH sensitive excipient that is 1,2-distearoyl-sn- glycero-3-phosphoethanolamine-poly(ethylene oxide) (DSPE-PEOz).

116. A method of preparing a plurality of particles or plurality' of liposomes (e.g., provided herein), the method comprising,a) combining an antioxidant, a polymer, an oil, an organic solvent, and an aqueous phase;b) evaporating the organic solvent, thereby forming the plurality of particles or plurality of liposomes,wherein the aqueous phase comprises a surfactant and water, and wherein the plurality of particles or plurality of liposomes comprise a polymer coat and a lipophilic core, wherein the lipophilic core comprises the antioxidant.VAZO-701-WO-PCTOl117. The method of any one of the preceding claims, wherein the polymer comprises PLGA.

118. The method of any one of the preceding claims, wherein the oil comprises labrifil M2125 CS oil, Epikuron El 45V.

119. The method of any one of the preceding claims, wherein the surfactant compnses polysorbate (e.g., polysorbate 80), or poloxamer (e.g., poloxamer 407).

120. The composition of any one of the preceding claims comprising DGG and hyaluronic acid (or a derivative thereof), such as a mucoadhesive thereof (if present).

121. The composition of any one of the preceding claims comprising DGG and CMC, such as a mucoadhesive thereof (if present).

122. A composition comprising a plurality of particles (e.g., nanoparticles), each of the plurality of particles comprising a substrate system selected from the group consisting of (a) pH-sensitive liposomes, (b) glycyrrhizic acid nanoparticles (GANP), (c) epigallocatechin gallate (EGCG) nanoparticles, (d) mesoporous silica-coated metal nanoparticles (e.g., MSPAg-NP), and (e) amphiphilic block copolymer (e.g., PEtOz-PLA) micelles.

123. The composition of claim 122, wherein the composition is a pharmaceutical or nutraceutical composition.

124. The composition of either one of claims 122 or 123, further comprising a transitional metal (e.g., silver).

125. The composition of claim 124, wherein the plurality of particles comprise the transitional metal (e.g.. silver).

126. The composition of any one of claims 122-125, wherein the plurality of particles are mesoporous coated metal nanoparticles comprising a transitional metal (e.g., silver) coated with the mesoporous material (e.g., silica or silicon).

127. The composition of any one of claims 122-125, wherein the composition comprises a mucoadhesive.

128. The composition of any one of claims 122-125, wherein the plurality of particles (e.g., nanoparticles) comprise a mucoadhesive.

129. The composition of any one of claims 122-125, wherein the composition provided comprises an antioxidant.VAZO-701-WO-PCTOl130. The composition of any one of claims 122-125, wherein the plurality of particles (e.g., nanoparticles) comprise an antioxidant.

131. The composition of any one of claims 122-125, wherein the compositoin comprises quercetin.

132. The composition of any one of claims 122-125, wherein the plurality' of particles (e.g., nanoparticles) comprise quercetin.

133. The composition of any one of claims 122-125, wherein the composition comprises glycyrrhizic acid.

134. The composition of any one of claims 122-125, wherein the plurality of particles (e.g., nanoparticles) comprise glycyrrhizic acid.

135. The composition of any one of claims 122-125, wherein the composition comprises epigallocatechin gallate (EGCG).

136. The composition of any one of claims 122-125, wherein the plurality of particles (e.g., nanoparticles) comprise EGCG.

137. The composition of any one of claims 122-125, wherein the plurality of particles (e.g., nanoparticles) comprise liposome(s).

138. The composition of any one of claims 122-125, wherein the plurality of particles (e.g., nanoparticles) comprise micelle(s).

139. The composition of any one of claims 122-138, wherein the composition is a nasal spray formulation.

140. A method of reducing viral exposure and / or reducing the chance of viral infection, the method comprising administering a composition of any one of claims 122-139 to an individual.

141. The method of claim 140, wherein the composition is administered by nasal or pulmonary administration.

Images