Non-crystalline amorphous iron oxide nanoparticle (naionp) compositions for oncologic disease states

Abstract

Disclosed herein are compositions and methods for deploying interventional agents into constrained biological states using non-crystalline amorphous iron oxide nanoparticles (NAIONPs). The NAIONPs comprise coordination-stabilized, aqueous colloidal dispersions lacking long-range crystalline order and presenting surface-accessible coordination sites for reversible or covalent association with one or more interventional agents. The compositions are configured to modify the biological context in which an interventional agent is presented, enabling functional engagement of agents whose deployment is limited when administered in isolation due to factors including impaired biodistribution, reduced stability, stress sensitivity, immune-mediated clearance, altered cellular responsiveness, or non-optimal exposure conditions. Interventional agents may include polynucleotides, peptides, proteins, small molecules, targeting moieties, radiologic agents, or combinations thereof. The disclosed compositions and methods are applicable to in vivo, ex vivo, and in vitro biological systems, including oncologic disease states such as primary tumors, metastatic disease, hematologic malignancies, and treatment-refractory cancers.

Description

[0001] Inventors Docket Number Filing Date

[0002]

[0003] D. Bonnin and D. Lazarus PAR-002-PCT January 14, 2026

[0004] NON-CRYSTALLINE AMORPHOUS IRON OXIDE NANOPARTICLE (NAIONP) COMPOSITIONS FOR ONCOLOGIC DISEASE STATES

[0005] This application claims priority to and the benefit of U. S. Provisional Patent Application Nos.

[0006] 63 / 833,777, filed January 14, 2025; 63 / 813,291, filed May 28, 2025; and 63 / 853,811, filed July 30, 2025, the entire contents of each of which are hereby incorporated by reference in their entirety for all purposes, including but not limited to support for compositions, constructs, methods of use, interventional agents, disease contexts, experimental examples, and figures disclosed herein.

[0007] Field of the Disclosure

[0008] The present disclosure relates to compositions comprising non-crystalline amorphous iron oxide nanoparticles (NAIONPs) and associated interventional agents, and to the use of such compositions in the context of oncologic disease states.

[0009] Background of the Disclosure

[0010] Oncologic disease states are frequently accompanied by systemic physiological dysfunction that extends beyond localized tumor burden. Such dysfunction is particularly pronounced in advanced or metastatic disease and may include profound metabolic, immunologic, and cellular stress. Among the most severe manifestations of this systemic disruption is cancer cachexia, a multifactorial wasting syndrome characterized by progressive loss of skeletal muscle mass, with or without loss of adipose tissue, that cannot be fully reversed by conventional nutritional support. These conditions contribute significantly to morbidity and mortality and often limit patient tolerance to oncologic interventions. Metastatic disease itself accounts for the majority of cancer-related deaths and is commonly associated with heightened biological fragility.

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[0014] D. Bonnin and D. Lazarus PAR-002-PCT January 14, 2026

[0015] While primary tumors may arise over extended periods through the accumulation of genetic alterations that promote survival and proliferation, progression to advanced oncologic disease states involves additional layers of regulatory complexity. In particular, genetic mutation alone is insufficient to account for the ability of tumor cells to migrate, adapt, and persist within distant or hostile microenvironments. Increasing evidence indicates that non-genetic regulatory mechanisms, including epigenetic modulation and altered RNA expression profiles, play a critical role in enabling cellular adaptation under stress. Short regulatory nucleic acids, such as microRNAs and other oligonucleotide species, have therefore been investigated as potential points of interventional engagement.

[0016] Despite advances in oncology therapeutics, many existing treatment strategies are constrained by their inability to function effectively in biologically compromised environments. In particular, the delivery, synthesis, or functional engagement of bioactive agents such as nucleic acids, peptides, or small molecules is frequently limited by carrier architectures that impose rigidity, restrict surface accessibility, or lack chemical adaptability under physiologic conditions. In some cases, limitations in oncologic intervention arise not from intrinsic inactivity of an interventional agent, but from pharmacokinetic, biodistribution, or deployment constraints that prevent effective engagement in oncologic disease states.

[0017] Traditional iron oxide nanoparticles are commonly based on crystalline lattice structures and fixed crosslinking strategies that constrain surface programmability and limit compatibility with dynamic or multivalent functionalization. Such architectures may exhibit reduced coordination accessibility, limited capacity for reversible interaction, and geometries poorly suited to modular workflows involving in situ conjugation, synthesis, or adaptive assembly of bioactive agents. These limitations can be especially problematic in oncologic contexts where cellular stress, metabolic fragility, or treatment-induced dysfunction necessitate greater chemical and functional flexibility.

[0018] Accordingly, there exists a need for compositions that support interventional engagement with oncologic disease states while accommodating the biological and chemical demands of stressed systems. In particular, there is a need for nanoparticle compositions that enable surface accessibility, coordinationbased association of functional agents, and integration into therapeutic or adjunctive workflows without reliance on crystalline ordering or non-aqueous processing. In certain embodiments, such compositions enable utilization of interventional agents that exhibit limited effectiveness or impractical deployment profiles when administered in isolation.

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[0022] D. Bonnin and D. Lazarus PAR-002-PCT January 14, 2026

[0023] The present disclosure addresses these needs through compositions comprising non-crystalline amorphous iron oxide nanoparticles (NAIONPs) that provide a chemically accessible and adaptable construct for association with interventional agents in oncologic disease states.

[0024] Summary of the Disclosure

[0025] The disclosed compositions and methods address deployment-limited interventional agents by decoupling biological execution from molecular identity.

[0026] Rather than relying on encapsulation, crystallinity, or fixed carrier architectures, the invention provides a coordination-accessible, non-crystalline colloidal construct that modifies the biological context in which an interventional agent is presented. This construct alters the conditions of exposure, interaction, and early biological response, enabling functional engagement in environments where conventional delivery approaches fail.

[0027] As a result, interventional agents that are otherwise limited by pharmacokinetics, biodistribution, stress sensitivity, regulatory instability, or system-level fragility are enabled to function within oncologic, immunologic, and other biologically compromised states.

[0028] Disclosed herein are compositions comprising non-crystalline amorphous iron oxide nanoparticles (NAIONPs) associated with one or more interventional agents for use in oncologic disease states. The disclosed compositions are suitable for association with a wide range of interventional agents, including nucleic acids, peptides, proteins, small molecules, targeting agents, or combinations thereof, and are configured to support interventional engagement in biologically compromised or treatment-stressed environments commonly associated with oncologic disease.

[0029] Oncologic disease states frequently involve systemic physiological dysfunction, metabolic reprogramming, immune dysregulation, and cellular stress that limit the effectiveness or tolerability of conventional therapeutic approaches. Such conditions may arise from primary malignancy, metastatic progression, or therapeutic intervention itself, and may include disease manifestations or sequelae— such as cachexia— that complicate effective treatment. In many cases, failure of an interventional agent to achieve functional engagement in these contexts reflects deployment limitations rather than intrinsic biological inactivity.

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[0033] D. Bonnin and D. Lazarus PAR-002-PCT January 14, 2026

[0034] The compositions disclosed herein provide a chemically accessible and adaptable construct for association with interventional agents without reliance on crystalline ordering, encapsulation, or non-aqueous processing. In certain embodiments, the NAIONPs are formulated as aqueous dispersions and present surface-accessible coordination sites suitable for reversible or covalent association with interventional agents, enabling modulation of exposure characteristics, interaction strength, temporal presentation, or release behavior in vivo, in vitro, or ex vivo.

[0035] In certain embodiments, the interventional agent comprises a polynucleotide selected from mRNA, antisense oligonucleotides, siRNA, microRNA, antisense microRNA sequences, aptamers, antagomirs, or nuclease guide strands, including modified or chemically substituted variants thereof. In other embodiments, the interventional agent comprises a small molecule, peptide, protein, antibody or fragment thereof, or ribonucleoprotein complex. In some embodiments, multiple interventional agents are associated with a single NAIONP construct.

[0036] The disclosed compositions may be incorporated into therapeutic, adjunctive, or combination workflows relevant to oncologic disease states, including contexts in which biological stress, altered cellular responsiveness, or treatment-induced fragility limits conventional delivery or administration approaches. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All publications, patent applications, patents, and other references cited herein are incorporated by reference in their entirety. In the event of a conflict, the present specification, including definitions, shall control.

[0037] Brief Description of the Drawings

[0038] Figure 1 illustrates representative dynamic light scatering (DLS) and zeta potential measurements of crude NAIONP following overnight quiescent rest at room temperature. No buffer exchange, purification, or filtration was performed prior to analysis, demonstrating the intrinsic colloidal stability of the pre-formed scaffold. Measurements were obtained on a Malvern Zetasizer (v8.02) at 25 °C using disposable sizing and zeta ceils. As shown, the hydrodynamic size distribution exhibits a monomodal intensity peak centered at approximately 45 nm, consistent with a stable amorphous nanoparticle population. Zeta potential analysis reveals a single electrophoretic mobility peak at -27 mV, indicating a uniformly anionic surface and the

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[0043] absence of aggregation or phase separation under aqueous storage conditions. These data confirm that the pre-formed amorphous scaffold maintains its size, charge, and colloidal integrity without post¬ synthesis processing, supporting its suitability as a substrate for post-synthetic phosphonate-anchored functionalization

[0044] Figure 2 shows viability of HT29 colorectal adenocarcinoma cells assessed 44 hours after a single exposure at the time of seeding to non-crystalline amorphous iron oxide nanoparticles (NAIONPs), either alone or associated with siRNA payloads. Cells were seeded at low density and exposed to media alone, NAIONPs without associated oligonucleotide, NAIONPs associated with a scrambled siRNA sequence, or NAIONPs associated with a siRNA targeting polo-like kinase 1 (siPLK1).

[0045] Contextual Description of NAIONP-Mediated Deployment Under Cellular Stress

[0046] Low-density cell seeding and early post-plating conditions represent a biologically constrained state characterized by acute cellular stress, altered metabolic demand, and heightened sensitivity to environmental perturbation. Under such conditions, cells frequently exhibit reduced viability, impaired proliferation, or altered responsiveness to exogenous agents, independent of the intrinsic activity of those agents. These constraints are commonly encountered not only in in vitro experimental systems, but also in vivo within tumor microenvironments, metastatic niches, and treatment-stressed tissues.

[0047] As illustrated in Figure 2, exposure of colorectal adenocarcinoma cells to non-crystalline amorphous iron oxide nanoparticles (NAIONPs) at the time of seeding was associated with preservation of cellular viability relative to media-only controls under low-density plating conditions. Importantly, this preservation was observed across conditions in which NAIONPs were administered alone as well as when NAIONPs were associated with RNA payloads, including scrambled siRNA sequences and siRNA targeting polo-like kinase 1 (PLK1). RNA payload exposure was normalized and expressed as per-cell oligonucleotide equivalents based on a defined nanoparticle loading ratio, enabling comparison across deployment conditions.

[0048] These observations indicate that NAIONP association enables presentation of interventional agents within a cellular context that would otherwise limit functional persistence or tolerability. Without being bound

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[0053] to a specific mechanism, the data support the concept that NAIONPs modify the biological context in which an interventional agent is encountered— such as local stress state, exposure kinetics, or cellular interaction dynamics— rather than relying solely on molecular encapsulation or carrier-mediated uptake.

[0054] In this regard, the NAIONPs disclosed herein function as deployment-enabling constructs, decoupling the biological execution of an interventional agent from its molecular identity. The ability to associate RNA payloads with NAIONPs while maintaining cellular viability under constrained conditions demonstrates that functional deployment may be achieved even in biological states where direct administration of the same agent would be ineffective, poorly tolerated, or misleading in experimental interpretation.

[0055] Accordingly, the compositions described herein are particularly suited for deployment-limited interventional agents in constrained biological states, including but not limited to low-density cellular systems, stressed tumor microenvironments, metastatic niches, treatment-refractory tissues, or other pathological or engineered contexts in which cellular responsiveness is altered.

[0056] Figure 3 illustrates the effects of administration of Antagonist 1, a glucagon-like peptide-1 receptor (GLP-1R) antagonist, in a colon-26 tumor-bearing murine model of cancer-associated cachexia. Antagonist 1 was administered intraperitoneally either at 3 mg / kg twice daily (bid) beginning on study day 5 following tumor implantation, or at 5 mg / kg bid beginning on study day 11, and compared to vehicle-treated tumor¬ bearing controls.

[0057] As shown, tumor-bearing animals receiving vehicle exhibited progressive loss of body weight and reduced food intake, consistent with the development of cachexia. In contrast, animals treated with Antagonist 1 demonstrated attenuation of body-weight loss and sustained or increased food consumption relative to vehicle-treated controls across both dosing regimens. These effects were observed despite continued tumor burden, indicating that GLP-1R antagonism can modulate systemic metabolic and appetite-related dysfunction associated with oncologic disease states.

[0058] Importantly, the dosing levels and routes required to achieve these effects in this model highlight a deployment limitation of small-molecule GLP-1R antagonists when administered in isolation, particularly in late-stage or treatment-stressed oncologic contexts. The data therefore support the relevance of GLP-1R antagonism as an interventional strategy for cancer-associated cachexia while simultaneously

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[0063] underscoring the need for alternative deployment approaches capable of modifying exposure characteristics, tolerability, or functional engagement.

[0064] Systemic Pathology and Deployment-Limited Interventional Agents

[0065] Oncologic disease states are frequently accompanied by constrained biological states that extend beyond localized tumor burden. These conditions may include metabolic dysregulation, appetite suppression, endocrine disruption, inflammatory signaling, immune imbalance, and stress-associated physiological decline. Collectively, these factors can create a constrained biological state in which otherwise active interventional agents exhibit reduced tolerability, impaired functional engagement, or diminished clinical utility when administered in isolation.

[0066] Cancer-associated cachexia represents one such constrained biological state. Cachexia is characterized by involuntary weight loss, muscle wasting, altered energy metabolism, and resistance to nutritional support, and is frequently observed in advanced malignancies. Importantly, cachexia may arise not only as a consequence of tumor growth, but also from tumor-derived signaling molecules and host stress responses that disrupt endocrine and metabolic regulation. These systemic effects can limit both patient resilience and the effective deployment of therapeutic agents.

[0067] As illustrated in Figure 3, pharmacologic antagonism of the GLP-1 receptor in colon-26 tumor-bearing mice resulted in increased food intake and partial preservation of body weight relative to vehicle-treated controls. These findings indicate that tumor-associated appetite suppression and metabolic dysfunction can be pharmacologically modulated, and further demonstrate that the biological environment in oncologic disease is not static, but may be shifted toward a more permissive or resilient state.

[0068] However, agents capable of modulating such systemic dysfunctions— including GLP-1R antagonists— ay themselves be deployment-limited due to pharmacokinetic constraints, tolerability concerns, stress sensitivity, or reduced functional persistence in diseased or treatment-stressed systems. In such contexts, failure of an agent to produce benefit may reflect limitations of deployment rather than intrinsic biological inactivity.

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[0073] The compositions disclosed herein address these limitations by providing a non-crystalline, coordination- accessible nanoparticie construct capable of associating with interventional agents and modifying the pathological context in which those agents are presented. By decoupling biological execution from molecular identity, NAIONP-associated constructs enable deployment of interventional agents into constrained biological states— such as cancer-associated cachexia — where conventional administration fails to achieve functional engagement.

[0074] In certain embodiments, NAIONP-associated interventional agents are used not only to directly target tumor cells, but also to modulate constrained biological states that impair therapeutic deployment, including metabolic stress, endocrine dysregulation, immune dysfunction, or treatment-induced fragility. This capability supports adjunctive, supportive, or enabling interventions that improve biological context, thereby enhancing the effectiveness of concurrent or subsequent oncologic therapies.

[0075] Detailed Description of the Disclosure

[0076] The present disclosure describes compositions comprising non-crystalline, amorphous iron oxide nanoparticles (NAIONPs) synthesized in aqueous solution under conditions that arrest particle growth prior to crystallization. The resulting nanoparticles are stabilized through coordination of multidentate ligands to ferric iron centers, yielding a flexible, surface-accessible colloidal architecture distinct from traditional crystalline iron oxide nanomaterials.

[0077] In certain embodiments, the NAIONPs are formed under kinetically controlled conditions that limit latice formation and magnetization, producing a non-magnetic, coordination-stabilized construct suitable for association with interventional agents. Ligand coordination provides structural stability while preserving surface accessibility, enabling reversible or covalent interaction with bioactive agents without reliance on rigid lattice structures or non-aqueous processing.

[0078] The disclosed NAIONP compositions are compatible with a range of chemical and biological association modes, including coordination-based binding, electrostatic interaction, or covalent conjugation. In some embodiments, ligand selection and surface chemistry are configured to support hydration control, charge moderation, or conjugation readiness, thereby enabling modulation of deployment characteristics such as exposure timing, interaction strength, or release behavior.

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[0083] Through these properties, the NAIONP compositions disclosed herein provide a chemically accessible construct for deployment of interventional agents in oncologic disease states, including environments characterized by biological stress, regulatory instability, or limited tolerance to conventional delivery approaches. The detailed embodiments described below illustrate representative NAIONP compositions and association strategies suitable for in vivo, in vitro, or ex vivo use, without limiting the scope of the disclosure.

[0084] Non-Crystalline Amorphous Iron Oxide Nanoparticles (NAIONPs)

[0085] The present disclosure utilizes non-crystalline, amorphous iron oxide nanoparticles (NAIONPs) as coordination-stabilized colloidal constructs for association with interventional agents. The NAIONPs are formed under aqueous conditions and lack long-range crystalline order, distinguishing them from conventional crystalline iron oxide nanoparticles.

[0086] In certain embodiments, the NAIONPs comprise iron predominantly in the Fe3+oxidation state and may optionally include dopant ions such as magnesium. Stabilization is achieved through multidentate ligand coordination, resulting in colloidally stable, surface-accessible particles compatible with physiologic environments. The absence of crystalline lattice structure preserves coordination accessibility and enables reversible or covalent association with bioactive agents including polynucleotides, peptides, proteins, or small molecules.

[0087] In some embodiments, the NAIONPs exhibit reduced magnetic properties, including low magnetic saturation, coercivity, and remanence, thereby minimizing magnetic interactions and associated biological effects. The particles may be formulated as substantially aggregate-free dispersions and, in certain embodiments, may be de-watered while retaining redispersibility and functional integrity.

[0088] Association of payloads with the NAIONPs may occur through electrostatic interaction, coordination-based binding, or covalent linkage. In representative embodiments, surface-presented reactive groups enable selective attachment of thiol- or amine-containing cargo. Such association supports controlled deployment of interventional agents without reliance on rigid lattice structures, polycationic carriers, or non-aqueous processing.

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[0093] The NAIONPs described herein provide a chemically accessible construct for deployment of interventional agents in biologically stressed or compromised environments, including oncologic disease states.

[0094] NAIONP Manufacture

[0095] Non-crystalline amorphous iron oxide nanoparticles (NAIONPs) described herein may be manufactured using a fully aqueous process that yields a coordination-stabilized colloidal construct suitable for association with interventional agents. In certain embodiments, iron salts are combined in water under controlled conditions that promote gradual oxidation and coordination-driven assembly, resulting in formation of non-crystalline, surface-accessible nanoparticles.

[0096] Particle formation is carried out under mild pH and temperature conditions and in the presence of coordinating ligands that stabilize pre-nucleation iron-oxygen assemblies and prevent crystallization. In some embodiments, additional ligands are included to impart hydrophilicity, charge stabilization, or reactive functionality to the particle surface. Dopant ions such as magnesium may be included to modulate colloidal behavior or biological interaction.

[0097] Following particle formation, the NAIONPs may be purified to remove unbound reagents and formulated as stable, substantially aggregate-free dispersions. Purification may include size-based separation, buffer exchange, or filtration. In certain embodiments, the nanoparticles are formulated in physiologically compatible buffers and may be sterile-filtered, de-watered, or lyophilized for storage and subsequent use. The resulting NAIONPs may exhibit hydrodynamic diameters ranging from about 20 nm to about 100 nm and surface charge characteristics compatible with biological deployment. The manufacturing methods described herein provide reproducible, scalable production of NAIONPs suitable for conjugation, association, or delivery of bioactive payloads in oncologic disease contexts.

[0098] Metastatic Disease

[0099] Metastatic cancer remains the leading cause of cancer-related mortality and is associated with limited therapeutic options and poor patient outcomes. While significant progress has been made in controlling primary tumors, metastatic disease is often resistant to conventional interventions, underscoring the need

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[0104] for alternative strategies capable of functioning under biologically compromised conditions. Metastasis is a complex, multi-step process in which cancer cells invade surrounding tissue, disseminate through vascular or lymphatic systems, evade immune surveillance, and adapt to foreign microenvironments at distant sites.

[0105] Although genetic mutations play a foundational role in tumor initiation and progression, metastasis is increasingly understood to be governed by non-genetic regulatory mechanisms rather than by the acquisition of additional driver mutations. Epigenetic reprogramming and altered RNA expression profiles enable cancer cells to dynamically adjust gene regulation, metabolic state, and stress response pathways, facilitating survival and persistence under hostile conditions. As a result, metastatic cells frequently exhibit regulatory and metabolic characteristics distinct from those of the primary tumor.

[0106] These regulatory adaptations contribute to therapy resistance, altered pharmacologic responsiveness, and increased fragility under intervention. Accordingly, limitations in the treatment of metastatic disease often arise not from the absence of biologically relevant targets, but from the inability to effectively deploy interventional agents within stressed and heterogeneous cellular environments. This regulatory plasticity reinforces the need for adaptable deployment architectures capable of accommodating variable biological states, exposure constraints, and dynamic interaction profiles characteristic of advanced oncologic disease.

[0107] GLP-1 Receptor Antagonists

[0108] The glucagon-like peptide-1 receptor (GLP-1R) is a G-protein-coupled receptor involved in systemic metabolic regulation, including modulation of insulin signaling, energy balance, and stress-responsive pathways. GLP-1R activity has been implicated in oncologic disease states associated with metabolic dysregulation and systemic physiological stress, including conditions such as cancer cachexia that frequently accompany advanced or metastatic disease.

[0109] Preclinical studies have demonstrated that antagonism of GLP-1R activity can modulate disease-associated metabolic pathways in oncologic contexts. In particular, administration of GLP-1R antagonists in tumor-bearing animal models has been shown to alter disease-associated phenotypes, providing biological validation of GLP-1R as an interventional target. However, such studies have also demonstrated that

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[0114] effective modulation often requires dosing regimens, routes of administration, or exposure profiles that are not clinically practical or compatible with the health status of patients suffering from advanced oncologic disease.

[0115] Accordingly, although GLP-1R antagonism is biologically validated, utilization of GLP-1R-directed interventional agents has been limited by deployment constraints rather than intrinsic inactivity of the target. Such constraints may include unfavorable pharmacokinetic or biodistribution profiles, limited persistence or stability in vivo, or insufficient engagement of tissues relevant to oncologic disease states, including immune-related or reticuloendothelial tissues.

[0116] GLP-1R antagonists suitable for use as interventional agents may exhibit competitive, non-competitive, allosteric, inverse, or expression-modulating activity. In certain embodiments, GLP-1R antagonism is achieved through direct inhibition of receptor activity. In other embodiments, GLP-1R antagonism is achieved through downregulation of receptor expression, including by RNA-based mechanisms such as antisense oligonucleotides, silencing RNAs, or regulatory microRNAs.

[0117] In certain embodiments, the GLP-1R antagonist comprises a small molecule, polypeptide, or polynucleotide. Non-limiting examples include small-molecule antagonists, peptide-based antagonists, antibodies or antibody fragments including nanobodies, and nucleic acid-based constructs configured to modulate GLP-1R expression or signaling. Such interventional agents may be associated with NAIONP constructs as disclosed herein to enable deployment in oncologic disease states characterized by biological stress, regulatory instability, or compromised tolerance to conventional intervention.

[0118] Accordingly, GLP-1R represents an interventional target whose therapeutic potential is frequently constrained by deployment limitations rather than lack of biological relevance. The compositions disclosed herein provide a platform for association and deployment of GLP-1R-directed interventional agents in oncologic disease states, enabling functional engagement under conditions in which administration of such agents in isolation is impractical or ineffective.

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[0123] RNA-based Interventional Agents

[0124] In certain embodiments, the interventional agent comprises a nucleic acid, including RNA or DNA, such as mRNA, antisense oligonucleotides, siRNA, miRNA, antagomirs, aptamers, guide RNAs, or combinations thereof. The nucleic acid may be single-stranded or double-stranded and may include naturally occurring or modified nucleotides, including modifications to the base, sugar, or backbone, as known in the art. In certain embodiments, a plurality of nucleic acid molecules is associated with each NAIONP in a dispersion, for example from about 1 to about 500 nucleic acid molecules per nanoparticle. In some embodiments, the nucleic acid molecules associated with a given nanoparticle are identical, while in other embodiments two or more distinct nucleic acid sequences are associated with a single nanoparticle. Association of nucleic acids with NAIONP compositions may be achieved through covalent or non-covalent interactions, including coordination-based, electrostatic, or linker-mediated attachment, using chemistries known in the art. Such association enables deployment of nucleic acid-based interventional agents in oncologic disease states without requiring chemical modification of the nucleic acid itself.

[0125] MicroRNAs

[0126] MicroRNAs (miRNAs) are small, non-coding RNA molecules that regulate gene expression at the post-transcriptional level and play critical roles in cellular regulation, including processes relevant to oncologic disease such as epithelial-to-mesenchymal transition (EMT), invasion, immune modulation, metabolic adaptation, and therapy resistance. Dysregulation of miRNA expression is a common feature of advanced and metastatic disease, where altered regulatory states enable tumor cells to adapt to biologically stressful and heterogeneous environments.

[0127] Certain miRNAs function as oncogenic regulators by promoting cellular behaviors associated with disease progression, including migration, invasion, and survival under stress, while other miRNAs act as suppressors of these processes by maintaining regulatory control over pathways that limit dissemination or enhance vulnerability to intervention. As a result, strategies aimed at modulating miRNA activity— either through inhibition of oncogenic miRNAs or restoration of regulatory miRNAs— have been investigated as potential interventional approaches in oncologic disease states.

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[0132] Interventional agents targeting miRNA activity may include antisense oligonucleotides, antagomirs, miRNA mimics, or other nucleic acid-based constructs designed to modulate regulatory RNA function. Such agents are often chemically modified to enhance stability, binding affinity, and resistance to degradation under physiological conditions. However, despite their biological relevance, miRNA-directed interventional agents frequently exhibit limited effectiveness when administered in isolation, due to challenges related to deployment, biodistribution, stability, and functional engagement in biologically compromised environments.

[0133] Accordingly, miRNAs and miRNA-targeting constructs represent a class of interventional agents whose functional potential is often constrained by deployment limitations rather than intrinsic biological inactivity. The compositions disclosed herein provide a platform for association and deployment of such interventional agents in oncologic disease states, enabling engagement under conditions characterized by regulatory instability, cellular stress, and altered responsiveness.

[0134] MicroRNA-10b

[0135] MicroRNA-10b (miR-10b) is a well-characterized oncogenic microRNA that plays a central role in metastatic progression across multiple cancer types. Numerous studies have demonstrated that miR-10b expression is elevated in metastatic cells and is associated with adverse clinical outcomes, including increased tumor burden, advanced disease stage, and reduced survival. miR-10b has been shown to regulate cellular behaviors critical to metastatic dissemination, including migration, invasion, and persistence within secondary microenvironments.

[0136] In addition to its role in promoting metastatic spread, miR-10b functions as a key regulator of metastatic cell viability. Unlike regulatory factors that primarily influence motility or invasion, miR-10b has been implicated in maintaining survival of disseminated tumor cells under biologically stressful conditions. This dual role in both dissemination and survival distinguishes miR-10b as a high-priority interventional target in advanced oncologic disease states.

[0137] Regulation of miR-10b expression is strongly influenced by non-genetic mechanisms, including epigenetic and transcriptional control pathways associated with cellular stress and phenotypic plasticity. Such regulatory flexibility enables tumor cells to dynamically modulate miR-10b activity in response to differing

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[0142] microenvironmental pressures encountered during metastatic progression. As a result, miR-10b activity is closely linked to regulatory instability and heterogeneity characteristic of advanced disease.

[0143] Interventional agents designed to inhibit miR-10b, including antisense oligonucleotides and antagomirs, have demonstrated potent and selective biological activity in preclinical models. However, despite strong biological validation, effective utilization of miR-10b-directed interventional agents has been limited by challenges related to deployment, including stability, biodistribution, and functional engagement within biologically compromised environments. These limitations have constrained translation despite demonstrated target relevance.

[0144] Accordingly, miR-10b represents an interventional target whose therapeutic potential is frequently limited by deployment constraints rather than intrinsic biological inactivity. The compositions disclosed herein provide a platform for association and deployment of miR-10b-directed interventional agents in oncologic disease states, enabling functional engagement under conditions characterized by metastatic stress, regulatory instability, and altered cellular responsiveness.

[0145] Pharmaceutical Compositions and Administration

[0146] Provided herein are compositions comprising NAIONPs associated with one or more interventional agents and at least one pharmaceutically acceptable carrier or diluent. Such compositions may be formulated in a manner suitable for the intended route of administration, including parenteral routes such as intravenous, intraarterial, intramuscular, intradermal, subcutaneous, or intraperitoneal administration. Pharmaceutically acceptable carriers or diluents may include, for example, sterile aqueous solutions, isotonic buffers, or excipients commonly used in injectable formulations. In certain embodiments, the compositions may include stabilizing agents, buffering agents, or tonicity-adjusting agents, as known in the art, provided that such components are compatible with the NAIONP dispersion and associated interventional agent.

[0147] The compositions may be provided in dosage unit form suitable for administration, including formulations contained in vials, syringes, or other delivery devices. The amount of interventional agent associated with

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[0152] the NAIONP composition may be selected based on the intended application and deployment context, without limitation to a particular therapeutic dose or biological outcome.

[0153] Methods of Use

[0154] Provided herein are methods for deploying interventional agents using NAIONP compositions in vivo, in vitro, or ex vivo, including extracellular or intracellular delivery. In certain embodiments, the methods comprise administering a composition comprising a NAIONP associated with one or more interventional agents to a biological system in the context of an oncologic disease state.

[0155] In some embodiments, the interventional agent comprises a GLP-1 receptor antagonist. Association of such interventional agents with NAIONP compositions enables administration and biological engagement in oncologic disease contexts without limitation to a particular therapeutic outcome or biological mechanism.

[0156] The methods described herein may be used to deliver interventional agents to tumors, tumor microenvironments, reticuloendothelial tissues, or other tissues associated with oncologic disease states. Administration may be performed via any suitable route, including parenteral routes, and may be adapted based on the intended deployment context.

[0157] In certain embodiments, the oncologic disease state is associated with a solid tumor or hematologic malignancy. Non-limiting examples include breast cancer, lung cancer, colorectal cancer, pancreatic cancer, liver cancer, kidney cancer, melanoma, glioblastoma, leukemia, lymphoma, ovarian cancer, gastric cancer, thyroid cancer, and metastatic variants thereof. The methods are not limited to a particular cancer type, stage, or site of disease.

[0158] The amount of interventional agent associated with the NAIONP composition and the conditions of administration may be selected based on the intended application and deployment context, without limitation to a particular dose, schedule, or therapeutic endpoint.

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[0163] Exemplary Embodiments

[0164] In certain embodiments, the disclosure relates to compositions comprising a non-crystalline, amorphous iron oxide nanoparticle (NAIONP) construct configured as a coordination-stabilized, aqueous-dispersible colloid lacking long-range crystalline order. The nanoparticle is synthesized entirely in aqueous solution under kinetically controlled, sub-nucleation conditions that suppress classical and non-classical nucleation pathways, resulting in a non-magnetic, coordination-stabilized colloidal structure rather than a crystalline lattice.

[0165] In certain embodiments, the nanoparticle comprises iron predominantly in the ferric (Fe3+) oxidation state. In some embodiments, the nanoparticle further comprises magnesium ions as dopants or coordination partners, which contribute to stabilization of the amorphous coordination network and modulation of surface coordination dynamics.

[0166] In certain embodiments, the nanoparticle is coordinated by a multivalent ligand architecture comprising multiple functional ligand classes distributed throughout and extending from a non-crystalline, coordination-stabilized iron oxide colloid. The ligand architecture may include one or more core-stabilizing ligands selected from phosphonates or phosphonates that coordinate directly to ferric iron centers and preserve the amorphous colloidal structure without formation of a crystalline lattice.

[0167] In further embodiments, the ligand architecture includes one or more zwitterionic ligands that promote hydration, charge balance, and resistance to nonspecific adsorption. In additional embodiments, the ligand architecture includes one or more hydrophilic sugar acids or related polyhydroxylated ligands that contribute to colloidal stability, hydration behavior, or reversible metal-mediated bridging. In certain embodiments, the ligand architecture further includes one or more thiol-reactive ligands, such as maleimide-containing phosphonates, configured to provide surface-accessible chemical handles for selective conjugation of interventional agents.

[0168] In some embodiments, the nanoparticle further comprises one or more polymeric or oligomeric ligands associated with the coordination-stabilized colloid. Such polymeric components may include dextran, dextran sulfate, or other polyol-based macromolecules that are coordinatively associated, interpenetrated, or surface-accessible within the amorphous nanoparticle structure, rather than forming

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[0173] a discrete encapsulating shell. These polymeric components may contribute to formulation stability, biocompatibility, hydration behavior, or downstream handling characteristics.

[0174] In certain embodiments, NAIONPs have a hydrodynamic diameter between about 12 nm and about 100 nm, including overlapping ranges of about 12-25 nm, 25-40 nm, 40-60 nm, 60-80 nm, or 80-100 nm. In some embodiments, the NAIONPs exhibit reduced magnetic properties relative to crystalline iron oxide nanoparticles.

[0175] In certain embodiments, the nanoparticle presents surface-accessible coordination or reactive sites suitable for covalent, coordinative, or reversible attachment of one or more interventional agents. Such interventional agents may include, without limitation, polynucleotides, peptides, proteins, small molecules, imaging agents, targeting ligands, or combinations thereof. Association may occur through thiol-reactive chemistry, amine-reactive chemistry, coordination-based binding, electrostatic interaction, or combinations of these mechanisms.

[0176] In certain embodiments, the NAIONP is provided in a payload-ready configuration suitable for subsequent conjugation, loading, surface-templated synthesis, reversible substrate binding, or modular functionalization by a user-selected interventional agent. Such formulations may be used in therapeutic, diagnostic, research, industrial, or manufacturing applications, including applications in which the nanoparticle serves as a deployable scaffold for site-specific or use-case-specific functionalization.

[0177] In certain embodiments, NAIONP compositions are used in oncologic disease states, including metastatic disease and associated manifestations such as cachexia, to deploy interventional agents whose efficacy is limited by pharmacokinetic, biodistribution, or deployment constraints when administered in isolation. In certain embodiments, the interventional agent comprises a small-molecule antagonist associated with glucagon-like peptide-1 (GLP-1) receptor biology. Such agents have demonstrated biological activity but may exhibit limitations related to biodistribution or deployment when administered alone. Association with NAIONP compositions enables cellular engagement of such agents in oncologic cell systems under tested conditions.

[0178] In certain embodiments, a non-crystalline amorphous iron oxide nanoparticle (NAIONP) is associated with a GLP-1 receptor antagonist and administered to a subject bearing a cachexia-inducing tumor, resulting in

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[0183] attenuation of tumor-associated body weight loss relative to an untreated or vehicle-treated tumor¬ bearing control.

[0184] In certain embodiments, association of a GLP-1 receptor antagonist with a NAIONP enables sustained or stabilized deployment of the antagonist, producing increased cumulative food intake in a tumor-bearing subject experiencing cachexia, following an initial transient reduction in food intake after treatment initiation.

[0185] In certain embodiments, NAIONP-associated delivery of a GLP-1 receptor antagonist maintains body weight in tumor-bearing subjects at a level between approximately 85% and 95% of baseline body weight over the course of tumor progression.

[0186] In certain embodiments, a GLP-1 receptor antagonist associated with a NAIONP is administered at a total effective daily dose lower than that required for free antagonist administration while achieving comparable attenuation of cachexia-associated weight loss.

[0187] In certain embodiments, NAIONP-mediated deployment of a GLP-1 receptor antagonist mitigates cachexia by counteracting appetite-suppressive signaling arising from gastrointestinal-derived tumors.

[0188] In certain embodiments, NAIONP association alters the pharmacokinetic and / or pharmacodynamic profile of a GLP-1 receptor antagonist such that inhibitory effects on GLP-1 and insulin-mediated anorexigenic signaling are sustained with reduced dosing frequency.

[0189] In certain embodiments, NAIONP-associated GLP-1 receptor antagonists reduce the combined anorexigenic effects of GLP-1 and insulin signaling in tumor-bearing subjects while improving tolerability relative to free antagonist administration.

[0190] In certain embodiments, the GLP-1 receptor antagonist is associated with the NAIONP via covalent attachment, coordination-based association, electrostatic interaction, or a combination thereof.

[0191] In certain embodiments, the NAIONP-associated GLP-1 receptor antagonist is administered via parenteral routes including intravenous, intraperitoneal, or subcutaneous administration.

[0192] In certain embodiments, NAIONP association enables redistribution of the GLP-1 receptor antagonist toward reticuloendothelial tissues, immune-associated compartments, lung, kidney, or tumor-adjacent microenvironments.

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[0197] In certain embodiments, NAIONP-mediated delivery reduces the requirement for twice-daily administration of a GLP-1 receptor antagonist while preserving cachexia-attenuating activity.

[0198] In certain embodiments, NAIONP-associated delivery addresses deployment limitations of free GLP-1 receptor antagonists, including poor tolerability, short half-life, or clinically impractical dosing regimens. In certain embodiments, the NAIONP functions as a deployment scaffold that preserves antagonist activity while modifying exposure timing, tissue distribution, or early stress responses encountered by the biological system.

[0199] In certain embodiments, NAIONP-associated GLP-1 receptor antagonists are used alone or in combination with additional interventional agents, including chemotherapeutics, metabolic modulators, anti¬ inflammatory agents, or nucleic acid-based therapeutics.

[0200] In certain embodiments, the NAIONP-associated GLP-1 receptor antagonist is used as part of a drug-rescue strategy, wherein a pharmacologically active agent with an otherwise impractical clinical profile is rendered therapeutically deployable through nanoparticle-mediated delivery.

[0201] In certain embodiments, the disclosed non-crystalline amorphous iron oxide nanoparticle (NAIONP) compositions are associated with one or more interventional agents configured to inhibit, modulate, or antagonize microRNA-10b (miR-10b) activity. In some embodiments, the interventional agent comprises an inhibitory oligonucleotide selected from an antisense oligonucleotide, antagomir, locked nucleic acid (LNA)-modified oligonucleotide, or other RNA-based inhibitor capable of binding to miR-10b or a precursor thereof.

[0202] In certain embodiments, NAIONPs provide a chemically accessible and adaptable construct for the association, stabilization, and deployment of miR-10b-directed interventional agents. The non-crystalline, coordination-stabilized architecture of NAIONPs enables association with miR-10b inhibitors without reliance on crystalline encapsulation or polycationic complexation, supporting reversible or covalent attachment, controlled presentation, and deployment in oncologic disease states.

[0203] In certain embodiments, the target microRNA is miR-10b, a well-characterized oncogenic miRNA implicated in tumor invasion, metastatic dissemination, and survival of metastatic cells across multiple cancer types. In certain embodiments, inhibition of miR-10b reduces metastatic cell survival, invasion,

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[0208] persistence at secondary sites, alters epithelial-mesenchymal transition (EMT), modulates cytoskeletal dynamics, or impairs survival of metastatic tumor cells.

[0209] In certain embodiments, the miR-10b-targeting oligonucleotide is between 12 and 30 nucleotides in length and is substantially complementary to a mature or precursor miR-10b sequence. Complementarity may be full or partial, provided sufficient binding to inhibit miR-10b function. In certain embodiments, the oligonucleotide is associated with the NAIONP via thiol-maleimide linkage, phosphonate coordination, electrostatic association, or a combination thereof.

[0210] In certain embodiments, NAIONP-associated miR-10b interventional agents are administered alone or in combination with additional interventional agents, including chemotherapeutics, metabolic modulators, immune-directed agents, radiotherapeutics, or additional nucleic acid payloads.

[0211] Provided herein are methods for in vivo, in vitro, or ex vivo delivery of one or more payloads using NAIONP dispersions described in this disclosure. In certain embodiments, the methods comprise extracellular or intracellular delivery of a functional payload using NAIONPs and are useful for preventing, treating, reducing, or alleviating symptoms associated with oncologic disease, including metastatic disease.

[0212] In certain embodiments, the nanoparticle dispersions enable sustained or controlled delivery of an anti-miR-10b payload to a target tissue, tumor, or tumor microenvironment. In further embodiments, the dispersions facilitate delivery of an anti-miR-10b payload to anatomical or physiological compartments that are conventionally difficult to access using standard drug delivery vehicles, including solid tumors, tumor cores, reticuloendothelial tissues, bone, lung, liver, or immune-associated tissues.

[0213] In certain embodiments, the nanoparticle dispersions are biocompatible and exhibit a circulation half-life ranging from approximately 0.25 hours to approximately 24 hours, depending on formulation, surface chemistry, and route of administration.

[0214] In certain embodiments, the disclosure relates to methods for treating metastatic disease comprising administering to a subject in need thereof a therapeutically effective amount of an anti-miR-10b payload associated with or delivered by a NAIONP. Treatment may be prophylactic or therapeutic in nature and may reduce disease burden, inhibit disease progression, delay onset or recurrence, or improve survival.

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[0219] In certain embodiments, treatment is achieved by administering one or more anti-miR-lOb payloads in an effective amount. An effective amount refers to an amount sufficient to produce a desired biological or therapeutic effect, as determined by disease state, subject characteristics, formulation, and route of administration. In certain embodiments, the anti-miR-10b payload is administered at a dose ranging from about 0.01 mg / kg to about 100 mg / kg at intervals selected from daily, alternate-day, weekly, bi-weekly, monthly, or longer intervals.

[0220] In certain embodiments, the methods disclosed herein are applicable to treatment of primary tumors and / or metastatic lesions, including tumors associated with distant metastatic sites such as bone, liver, lung, brain, or lymphatic tissue. In certain embodiments, the disease treated is a solid tumor or hematologic malignancy characterized by elevated miR-lOb activity or metastatic behavior.

[0221] In certain embodiments, NAIONPs are associated with one or more interventional agents configured to modulate resistance mechanisms in tumor cells. In some embodiments, the interventional agent comprises an inhibitory RNA selected from siRNA, antisense oligonucleotide, antagomir, or miRNA mimic, wherein the inhibitory RNA targets a gene or regulatory pathway associated with therapeutic resistance. In certain embodiments, the resistance mechanism comprises drug efflux or reduced intracellular retention of therapeutic agents. In such embodiments, NAIONP-associated interventional agents are configured to reduce expression or activity of transporters or regulatory proteins involved in cellular efflux, thereby enhancing intracellular exposure to co-administered or sequentially administered therapeutic agents.

[0222] In certain embodiments, resistance is associated with suppression of programmed cell death pathways. In such embodiments, NAIONP-associated interventional agents are configured to reduce expression of anti-apoptotic factors or to restore apoptotic competency, thereby lowering the threshold for therapeutic response.

[0223] In certain embodiments, resistance is associated with phenotypic plasticity, stress-adapted cellular states, or EMT-associated transcriptional programs. In such embodiments, NAIONP-associated interventional agents are configured to modulate regulatory RNAs or transcriptional pathways that govern cellular state transitions, thereby restoring sensitivity to therapeutic intervention.

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[0228] In certain embodiments, resistance is associated with immune evasion or immune suppression within the tumor microenvironment. In such embodiments, NAIONP-associated interventional agents are configured to modulate immune-regulatory pathways, either by reducing expression of immunosuppressive signals or by enhancing immune-activating signals, thereby supporting durable interventional engagement. In certain embodiments, NAIONP-associated resistance-modulating agents are used alone or in combination with additional interventional agents, including chemotherapeutics, targeted therapies, metabolic modulators, or immune-directed agents. Such combinations may be administered sequentially or contemporaneously and may be configured to restore or enhance responsiveness in oncologic disease states.

[0229] In certain embodiments, NAIONPs are associated with one or more inhibitory RNAs configured to reduce expression of a target gene product implicated in an oncologic disease state. In some embodiments, the inhibitory RNA comprises an siRNA, shRNA, antisense oligonucleotide, antagomir, or other gene-silencing oligonucleotide. In certain embodiments, the inhibitory RNA is about 15-30 nucleotides in length (e.g., 17-24 nucleotides) and is sufficiently complementary to a target transcript to mediate gene suppression, including by RISC-dependent cleavage or translational repression. In some embodiments, the target gene product comprises a receptor, enzyme, transcription factor, immune marker, oncogene, or other disease- associated protein, including, without limitation, EGFR, CD20, PD-L1, CD47, KRAS, MYC, BCL2, VEGF, or combinations thereof.

[0230] In certain embodiments, NAIONPs disclosed herein may include one or more radiolabel atoms for imaging, diagnostic, or therapeutic applications. Radiolabels may be incorporated within, coordinated to, or associated with the NAIONP via direct coordination chemistry, non-covalent interactions, or through one or more chemical linkers.

[0231] In certain embodiments, radiolabels associate directly with the NAIONP through coordination to surface- exposed ligands, including phosphonate or phosphonate groups present within or extending from the coordination-stabilized colloid. In such embodiments, the radiometal is bound via direct coordination interactions with the NAIONP ligand architecture, without the use of exogenous chelators.

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[0236] In other embodiments, radiolabels are incorporated via one or more chelating agents, including but not limited to DOTA, NOTA, or derivatives thereof, which may be covalently or coordinatively associated with the NAIONP surface.

[0237] The number of radiolabel atoms associated with a given NAIONP may vary depending on ligand density, coordination strategy, steric accessibility, and stability considerations. In certain embodiments, NAIONPs include a plurality of radiolabel atoms sufficient to enable imaging or therapeutic utility while maintaining colloidal stability and functional surface logic.

[0238] In certain embodiments, the radiolabel comprises a radionuclide suitable for positron emission tomography (PET), single-photon emission computed tomography (SPECT), or radiotherapeutic applications. Selection of the radionuclide may be based on physical half-life, emission characteristics, and compatibility with the pharmacokinetic profile of the NAIONP construct.

[0239] Illustrative radionuclides include, but are not limited to, copper-64 (Cu-64), fluorine-18 (F-18), scandium- 44 (Sc-44), cobalt-55 (Co-55), zirconium-89 (Zr-89), lutetium-177 (Lu-177), yttrium-90 (Y-90), terbium-161 (Tb-161), bismuth-213 ( Bi-213), lead-212 (Pb-212), actinium-225 (Ac-225), rhenium-188 (Re-188), copper- 67 (Cu-67), thallium-201 (Tl-201), and niobium-90 (Nb-90).

[0240] In certain embodiments, the radiolabel is copper-64, incorporated either through direct coordination to phosphonate ligands present on the NAIONP surface or via chelator-mediated attachment.

[0241] In certain embodiments, NAIONP-associated radiolabels are used for tracking biodistribution, pharmacokinetics, tissue accumulation, or clearance of the nanoparticle construct. In certain embodiments, NAIONP-associated radiolabels are used for therapeutic radiation delivery, optionally in combination with one or more additional payloads carried by the NAIONP.

[0242] In certain embodiments, the compositions and methods disclosed herein are used to deliver oligonucleotides that modulate miRNA activity, including antisense oligonucleotides, antagomirs, miRNA mimics, sponge constructs, or functionally equivalent inhibitors or restoratives. Such oligonucleotides may inhibit oncogenic miRNAs or restore the function of tumor-suppressive miRNAs.

[0243] In certain embodiments, NAIONP-based compositions are configured to bind, sequester, or inhibit target miRNAs through Watson-Crick base pairing using sense or antisense sequences. In other embodiments,

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[0248] NAIONP compositions deliver miRNA mimics to restore downregulated miRNA activity in diseased cells. Oligonucleotides may be single-stranded or double-stranded and may incorporate chemical modifications to enhance stability, binding affinity, or resistance to nuclease degradation, including but not limited to 2'- O-methyl, 2'-O-methoxyethyl, phosphorothioate linkages, locked nucleic acids (LNA), or combinations thereof.

[0249] In certain embodiments, the miRNA targeted or delivered by the NAIONP is selected from oncogenic or tumor-suppressive miRNAs associated with cancer, including but not limited to members of the miR-9, miR-10, miR-17-92, miR-21, miR-26, miR-29, miR-92, miR-125, miR-130, miR-155, miR-181, miR-200, miR-210, miR-221 / 222, miR-335, miR-498, miR-504, or miR-224 / 452 families.

[0250] In certain embodiments, the disclosed non-crystalline amorphous iron oxide nanoparticle (NAIONP) compositions are associated with one or more interventional agents configured to inhibit, modulate, or antagonize biological pathways implicated in oncologic disease, tumor resistance, or disease persistence. In some embodiments, the interventional agent comprises a nucleic acid-based payload selected from siRNA, antisense oligonucleotides, antagomirs, microRNA mimics, locked nucleic acid (LNA)-modified oligonucleotides, or functionally equivalent RNA-based agents capable of modulating gene expression or signaling pathways.

[0251] In certain embodiments, NAIONPs provide a chemically accessible and adaptable construct for the association, stabilization, and deployment of such interventional agents. The non-crystalline, coordination-stabilized architecture of NAIONPs enables association with nucleic acid or small-molecule payloads without reliance on crystalline encapsulation, lipid nanoparticle assembly, or polycationic complexation, thereby supporting reversible or covalent attachment, controlled presentation, and deployment in oncologic disease states.

[0252] In certain embodiments, the interventional agent targets one or more ATP-binding cassette (ABC) transporters associated with multidrug resistance. In some embodiments, the target is selected from ABCB1 (P-glycoprotein), ABCG2 (BCRP), or ABCC1 (MRP1). Inhibition or downregulation of these transporters reduces drug efflux, enhances intracellular retention of therapeutic agents, and restores sensitivity to chemotherapeutics in resistant tumor cells.

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[0257] In certain embodiments, the interventional agent comprises an siRNA or antisense oligonucleotide substantially complementary to an mRNA encoding an ABC transporter. In certain embodiments, NAIONP- mediated delivery of such agents reduces transporter expression, reverses multidrug resistance phenotypes, or enhances the efficacy of co-administered cytotoxic or targeted therapies.

[0258] n certain embodiments, the interventional agent modulates epithelial-mesenchymal transition (EMT) or tumor cell plasticity. In some embodiments, the agent comprises an siRNA targeting transcriptional regulators selected from YAP1, ZEB1, SNAIL, or TWIST. In other embodiments, the interventional agent comprises a microRNA mimic selected from the miR-200 family, miR-34a, or functionally related tumor¬ suppressive microRNAs.

[0259] In certain embodiments, NAIONP-mediated delivery of EMT-modulating agents promotes reversion of mesenchymal or stem-like tumor cells toward a drug-sensitive epithelial phenotype, reduces invasive behavior, suppresses metastatic dissemination, or restores therapeutic responsiveness.

[0260] In certain embodiments, the interventional agent targets anti-apoptotic or survival-associated genes. In some embodiments, the target is selected from BCL2, MCL1, or BIRC5 (survivin). In certain embodiments, the interventional agent comprises an siRNA or antisense oligonucleotide that lowers the apoptotic threshold of tumor cells.

[0261] In other embodiments, the interventional agent comprises a microRNA mimic, such as miR-34a, that endogenously suppresses multiple apoptotic inhibitors. In certain embodiments, NAIONP-mediated delivery of such agents enhances sensitivity to chemotherapy, radiotherapy, or immune-mediated killing. In certain embodiments, the interventional agent targets one or more oncogenic driver genes. In some embodiments, the target is selected from KRAS (including mutant alleles such as G12D), EGFR (including resistance mutations such as T790M), BRAF (including V600E), or ALK fusion genes.

[0262] In certain embodiments, the NAIONP is further associated with targeting ligands, peptides, antibodies, or aptamers that enhance selective delivery to tumor cells expressing the corresponding oncogenic alteration. In certain embodiments, NAIONP-mediated delivery enables allele-specific silencing of oncogenic drivers with reduced off-target toxicity.

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[0267] In certain embodiments, the interventional agent modulates the tumor immune microenvironment. In some embodiments, the agent comprises an siRNA targeting immunosuppressive molecules selected from PD-L1, TGF-β, or IDO1. In other embodiments, the agent comprises an mRNA encoding immune-activating proteins such as IL-12, GM-CSF, or antibody fragments targeting immune checkpoints.

[0268] In certain embodiments, NAIONP-mediated delivery of immune-modulatory agents enhances immune cell infiltration, reverses tumor-mediated immune suppression, or promotes durable anti-tumor immune responses.

[0269] In certain embodiments, the interventional agent is associated with the NAIONP via thiol-maleimide linkage, phosphonate coordination, electrostatic association, chelation-mediated attachment, or combinations thereof. In certain embodiments, the oligonucleotide payload is between about 12 and 30 nucleotides in length and is substantially complementary to a target nucleic acid sequence.

[0270] Provided herein are methods for in vivo, in vitro, or ex vivo delivery of one or more payloads using NAIONP dispersions described in this disclosure. In certain embodiments, the methods comprise extracellular or intracellular delivery of functional payloads and are useful for preventing, treating, reducing, or alleviating symptoms associated with oncologic disease, including metastatic disease and treatment-resistant malignancies.

[0271] In certain embodiments, NAIONP dispersions enable sustained or controlled delivery of interventional agents to target tissues, tumors, or tumor microenvironments, including anatomical or physiological compartments that are conventionally difficult to access using standard drug delivery vehicles, such as solid tumors, tumor cores, bone, lung, liver, brain, reticuloendothelial tissues, or immune-associated tissues.

[0272] In certain embodiments, the nanoparticle dispersions are biocompatible and exhibit a circulation half-life ranging from approximately 0.25 hours to approximately 24 hours, depending on formulation, surface chemistry, and route of administration.

[0273] In certain embodiments, treatment is achieved by administering one or more NAIONP-associated interventional agents in a therapeutically effective amount. In certain embodiments, the dose ranges from about 0.01 mg / kg to about 100 mg / kg, administered at intervals selected from daily, alternate-day, weekly,

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[0278] bi-weekly, monthly, or longer intervals. Treatment may be prophylactic or therapeutic and may reduce disease burden, inhibit disease progression, delay onset or recurrence, or improve survival.

[0279] In certain embodiments, the disclosed non-crystalline amorphous iron oxide nanoparticle (NAIONP) compositions are associated with one or more small-molecule chemotherapeutic agents. In some embodiments, the small-molecule chemotherapeutic is configured for association, stabilization, and deployment via the coordination-stabilized, non-crystalline architecture of the NAIONP. Association may occur through covalent attachment, coordination-based interaction, reversible adsorption, or encapsulation within a polymeric or ligand-mediated surface domain.

[0280] In certain embodiments, NAIONP-mediated deployment of small-molecule chemotherapeutics modifies the pharmacokinetic, biodistribution, tolerability, or effective concentration profile of the chemotherapeutic relative to administration of the small molecule in isolation.

[0281] In certain embodiments, the small-molecule chemotherapeutic comprises a DNA-damaging or DNA- interacting agent. Such agents may include alkylating agents, platinum-based compounds, intercalators, or topoisomerase poisons. In certain embodiments, NAIONP-mediated delivery enhances tumor localization, reduces systemic toxicity, or enables sustained exposure of tumor cells to DNA-damaging stress.

[0282] In certain embodiments, the small-molecule chemotherapeutic comprises an antimetabolite that interferes with nucleotide synthesis, DNA replication, or RNA transcription. In certain embodiments, NAIONP association improves intracellular retention, synchronizes exposure with tumor cell cycling, or reduces dose-limiting toxicity.

[0283] In certain embodiments, the small-molecule chemotherapeutic disrupts mitotic spindle formation or cytoskeletal dynamics. In certain embodiments, NAIONP-mediated delivery enhances tumor-selective exposure, reduces off-target neuropathy, or enables combination deployment with agents that sensitize cells to mitotic stress.

[0284] In certain embodiments, the small-molecule chemotherapeutic comprises a targeted inhibitor of a signaling kinase, growth factor receptor, or oncogenic enzyme. In certain embodiments, NAIONP-mediated delivery enables altered tissue distribution, prolonged target engagement, or coordinated deployment with nucleic acid payloads targeting compensatory pathways.

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[0289] In certain embodiments, the small-molecule chemotherapeutic comprises a hormonal agent or metabolic modulator that alters tumor growth, nutrient utilization, or endocrine signaling. In certain embodiments, NAIONP-mediated delivery enables modulation of exposure timing, tissue specificity, or combinatorial use with cytotoxic or RNA-based agents.

[0290] In certain embodiments, the small-molecule chemotherapeutic is selected from alkylating agents including cyclophosphamide, ifosfamide, melphalan, or temozolomide.

[0291] In certain embodiments, the small-molecule chemotherapeutic is selected from platinum-based compounds including cisplatin, carboplatin, or oxaliplatin.

[0292] In certain embodiments, the small-molecule chemotherapeutic is selected from antimetabolites including 5-fluorouracil, capecitabine, methotrexate, gemcitabine, cytarabine, or pemetrexed.

[0293] In certain embodiments, the small-molecule chemotherapeutic is selected from topoisomerase inhibitors including doxorubicin, epirubicin, daunorubicin, irinotecan, or etoposide.

[0294] In certain embodiments, the small-molecule chemotherapeutic is selected from mitotic inhibitors including paclitaxel, docetaxel, vincristine, vinblastine, or eribulin.

[0295] In certain embodiments, the small-molecule chemotherapeutic is selected from targeted inhibitors including tyrosine kinase inhibitors, serine / threonine kinase inhibitors, or metabolic enzyme inhibitors, including imatinib, erlotinib, gefitinib, osimertinib, sorafenib, vemurafenib, dabrafenib, or trametinib. In certain embodiments, the small-molecule chemotherapeutic is selected from hormonal or endocrine agents including tamoxifen, fulvestrant, aromatase inhibitors, or androgen signaling inhibitors.

[0296] In certain embodiments, the NAIONP-associated small-molecule chemotherapeutic is administered alone or in combination with one or more additional interventional agents, including RNA-based therapeutics, immune-modulatory agents, radiotherapeutics, or metabolic modulators.

[0297] In certain embodiments, NAIONP-mediated deployment enables coordinated or sequential exposure of tumor cells to small-molecule chemotherapeutics and nucleic acid payloads, thereby overcoming resistance mechanisms, enhancing cytotoxic efficacy, or reducing systemic toxicity.

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[0302] In certain embodiments, NAIONP-mediated delivery enables deployment of small-molecule chemotherapeutics to anatomical or physiological compartments that are conventionally difficult to access using standard formulations, including solid tumors, tumor cores, bone, lung, liver, brain, or immune- associated tissues.

[0303] In certain embodiments, the disclosed non-crystalline amorphous iron oxide nanoparticle (NAIONP) compositions are associated with one or more targeting moieties configured to influence biodistribution, tissue localization, cellular uptake, or intracellular trafficking of the nanoparticle or an associated payload. In certain embodiments, the targeting moiety facilitates preferential interaction with a target cell population, tissue, microenvironment, or disease-associated structure. Targeting may be receptor-mediated, affinity-based, microenvironment-responsive, or driven by physicochemical compatibility rather than strict receptor specificity.

[0304] In certain embodiments, targeting moieties are associated with the NAIONP via covalent, coordinative, or reversible interactions and are presented on the nanoparticle surface in a manner that preserves biological activity while maintaining colloidal stability.

[0305] In certain embodiments, the targeting moiety comprises a peptide or polypeptide capable of interacting with a cell-surface receptor, extracellular matrix component, or disease-associated molecular structure. In some embodiments, the peptide comprises a linear peptide, cyclic peptide, stapled peptide, or peptide mimetic. In certain embodiments, peptides are selected to bind integrins, growth factor receptors, tumor- associated antigens, vascular markers, or stromal components.

[0306] In certain embodiments, peptide targeting moieties are conjugated to the NAIONP via thiol-reactive chemistry, amine-reactive chemistry, or coordination-mediated attachment.

[0307] In certain embodiments, the targeting moiety comprises an antibody, antibody fragment, or antibody- derived binding domain.

[0308] In some embodiments, the targeting moiety comprises a Fab, scFv, single-domain antibody, nanobody, or other engineered binding protein. In certain embodiments, nanobodies are preferred due to reduced size, improved tissue penetration, and compatibility with dense or multivalent surface presentation.

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[0313] In certain embodiments, antibody-based targeting moieties are conjugated to the NAIONP via site-specific chemistry, including thiol-maleimide coupling, enzymatic ligation, or engineered coordination handles. In certain embodiments, the targeting moiety comprises a nucleic acid aptamer configured to bind a target molecule with high affinity and specificity.

[0314] In some embodiments, aptamers are RNA or DNA aptamers and may be chemically modified to enhance nuclease resistance, stability, or binding affinity. In certain embodiments, aptamers serve dual roles as targeting moieties and functional RNA payloads.

[0315] In certain embodiments, the targeting moiety comprises a small molecule, metabolite analog, or ligand capable of binding a cell-surface receptor or transporter.

[0316] In some embodiments, such ligands include vitamins, sugars, lipids, hormones, or receptor-binding small molecules. In certain embodiments, the targeting moiety exploits differential transporter expression, metabolic demand, or receptor density rather than exclusive receptor expression.

[0317] In certain embodiments, targeting is achieved through interaction with disease-associated microenvironmental features rather than a specific receptor.

[0318] In some embodiments, targeting moieties are responsive to pH, redox state, enzymatic activity, ionic composition, hypoxia, or extracellular matrix composition characteristic of tumors, inflamed tissue, or diseased organs.

[0319] In certain embodiments, targeting moieties are presented on the NAIONP surface in a spatially accessible and functionally active configuration enabled by the coordination-stabilized, non-crystalline architecture of the nanoparticle.

[0320] In certain embodiments, the NAIONP allows controlled surface density, orientation, or multivalency of targeting moieties without reliance on crystalline facet geometry or polycationic scaffolds.

[0321] In certain embodiments, targeting moieties are attached via: thiol-maleimide chemistry, phosphonate or metal coordination, reversible electrostatic association, or combinations thereof.

[0322] In certain embodiments, targeting moieties may be reversibly associated, enabling exchange, removal, or reconfiguration prior to or after deployment.

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[0327] In certain embodiments, NAIONPs are associated with two or more targeting moieties configured to engage distinct biological features, including combinations of: peptide + nanobody, aptamer + peptide, receptor-binding ligand + microenvironment-responsive element.

[0328] In certain embodiments, targeting moieties are used in combination with therapeutic payloads, including RNA-based agents, small-molecule chemotherapeutics, immune modulators, or radiolabels.

[0329] In certain embodiments, targeting moieties are used to bias NAIONP accumulation while therapeutic specificity is provided by the associated payload.

[0330] In certain embodiments, targeting moieties are selected based on functional outcomes, including enhanced uptake, retention, penetration, or intracellular access, rather than exclusive binding to a single receptor.

[0331] In certain embodiments, the targeting moiety improves delivery efficiency, reduces off-target exposure, or alters intracellular routing without requiring absolute specificity for a given cell type.

[0332] In certain embodiments, targeting moieties are configured to support deployment of NAIONPs in disease contexts where receptor heterogeneity, mutation, or downregulation limits the effectiveness of conventional targeting strategies.

[0333] In certain embodiments, the compositions and methods disclosed herein are used for deployment of one or more interventional agents into a constrained biological state associated with an oncologic disease. Such oncologic disease states may include, without limitation, primary solid tumors, metastatic disease, hematologic malignancies, or treatment-refractory cancers, wherein cellular stress, metabolic dysregulation, immune dysfunction, altered tissue architecture, or therapeutic burden limits effective deployment of the interventional agent when administered without the NAIONPs.

[0334] In certain embodiments, the oncologic disease state comprises metastatic disease, including metastatic dissemination to bone, liver, lung, brain, lymphatic tissue, or combinations thereof. In such embodiments, the constrained biological state may be characterized by altered vascular permeability, hypoxia, immune suppression, or stress-adapted tumor cell phenotypes that impair functional engagement of interventional agents delivered in isolation.

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[0339] In certain embodiments, the oncologic disease state comprises treatment-induced or disease-associated cachexia, metabolic wasting, or systemic physiological dysfunction that limits tolerability, stability, or efficacy of interventional agents. In such embodiments, association of the interventional agent with the NAIONPs enables deployment under conditions of systemic stress, altered nutrient signaling, endocrine dysregulation, or inflammatory burden.

[0340] In certain embodiments, the constrained biological state comprises an immunologically altered oncologic environment, including immune-excluded tumors, immunosuppressed microenvironments, or treatment- altered immune states resulting from chemotherapy, radiotherapy, or immunotherapy. In such embodiments, the NAIONP-associated interventional agent is deployed in a context where immune dysfunction or immune exhaustion limits conventional delivery or activity.

[0341] In certain embodiments, the constrained biological state comprises a post-treatment or post-intervention oncologic state, including residual disease, minimal residual disease, or therapy-resistant cellular populations. In such embodiments, the NAIONP composition enables deployment of interventional agents into biologically altered systems that persist following prior therapeutic exposure.

[0342] In certain embodiments, the constrained biological state is present ex vivo or in vitro, including tumor-derived cell cultures, organoids, explants, engineered tissue models, or co-culture systems that recapitulate stress, metabolic limitation, immune interaction, or treatment-induced dysfunction observed in vivo. In such embodiments, the NAIONP compositions enable functional deployment of interventional agents under experimentally or pathologically constrained conditions.

[0343] In certain embodiments, while the present disclosure is directed to oncologic disease states, the constrained biological state may share features with other disease-associated or engineered conditions characterized by cellular stress, immune dysregulation, metabolic imbalance, or altered tissue architecture, and the NAIONP-based deployment architecture described herein is applicable to such contexts as further disclosed in related applications.

[0344] n certain embodiments, the disclosure relates to compositions for the deployment of one or more interventional agents into a constrained biological state. The compositions comprise a dispersion of noncrystalline amorphous iron oxide nanoparticles (NAIONPs) and one or more interventional agents associated with the NAIONPs.

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[0349] In certain embodiments, the constrained biological state limits functional deployment of the interventional agent when the agent is administered in isolation, without association with the NAIONPs. Such limitations may arise from non-optimal exposure, instability, clearance, stress sensitivity, or context- dependent biological fragility of the interventional agent.

[0350] In certain embodiments, association of the interventional agent with the NAIONPs enables functional engagement of the agent within the constrained biological state by modifying the deployment context rather than the intrinsic molecular identity of the agent.

[0351] In certain embodiments, the interventional agent associated with the NAIONPs is selected from a polynucleotide, peptide, protein, small molecule, targeting moiety, radiologic agent, or a combination thereof.

[0352] In certain embodiments, the interventional agent comprises one or more polynucleotides, including siRNA, antisense oligonucleotides, microRNA inhibitors, microRNA mimics, mRNA, guide RNAs, or combinations thereof, including chemically modified or substituted variants.

[0353] In certain embodiments, the interventional agent comprises peptides or polypeptides, including signaling peptides, agonists, antagonists, enzymes, or functional fragments thereof.

[0354] In certain embodiments, the interventional agent comprises proteins, including antibodies, antibody fragments, nanobodies, cytokines, growth factors, or ribonucleoprotein complexes.

[0355] In certain embodiments, the interventional agent comprises small-molecule agents, including chemotherapeutics, metabolic modulators, sensitizing agents, or pathway inhibitors.

[0356] In certain embodiments, the interventional agent comprises one or more targeting moieties, including peptides, antibodies, nanobodies, aptamers, affinity ligands, or combinations thereof.

[0357] In certain embodiments, the interventional agent comprises a radiologic agent, including radionuclides, radiotherapeutic agents, radiotracers, or combinations thereof.

[0358] In certain embodiments, two or more interventional agents selected from different classes are associated with a single NAIONP dispersion.

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[0363] In certain embodiments, the interventional agent is associated with the NAIONPs via reversible coordination chemistry.

[0364] In certain embodiments, the interventional agent is associated with the NAIONPs via covalent linkage. In certain embodiments, the interventional agent is associated with the NAIONPs via a combination of reversible coordination and covalent linkage.

[0365] In certain embodiments, the NAIONPs present surface-accessible coordination sites that permit reversible association, exchange, or modulation of binding strength under biological conditions.

[0366] In certain embodiments, the constrained biological state is associated with an oncologic disease.

[0367] In certain embodiments, the oncologic disease is selected from primary solid tumors, metastatic disease, hematologic malignancies, or treatment-refractory cancers.

[0368] In certain embodiments, the constrained biological state comprises a disease-associated systemic condition that limits tolerability or functional deployment of the interventional agent when administered without the NAIONPs.

[0369] In certain embodiments, the constrained biological state comprises metastatic disease or a metastatic tumor microenvironment.

[0370] In certain embodiments, the interventional agent comprises a miR-10b-targeting oligonucleotide configured to inhibit or modulate miR-10b activity in metastatic tumor cells.

[0371] In certain embodiments, the interventional agent comprises a glucagon-like peptide-1 (GLP-1) receptor antagonist, and the composition is configured for deployment in an oncologic disease state characterized by metabolic or systemic dysfunction.

[0372] In certain embodiments, the interventional agent comprises a radiologic agent selected from radionuclides, radiotherapeutic moieties, or combinations thereof.

[0373] In certain embodiments, the radiologic agent is configured for diagnostic, therapeutic, or theranostic applications when associated with the NAIONPs.

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[0378] In certain embodiments, the disclosure relates to methods of deploying a deployment-limited interventional agent in a constrained biological state.

[0379] In certain embodiments, the method comprises associating the interventional agent with a NAIONP composition and exposing a biological system to the NAIONP composition.

[0380] In certain embodiments, the biological system comprises a living subject.

[0381] In certain embodiments, the biological system comprises cultured cells, organoids, tissue explants, or engineered biological constructs.

[0382] In certain embodiments, the disclosure relates to a deployable interventional construct comprising a dispersion of NAIONPs synthesized under aqueous, sub-nucleation conditions.

[0383] In certain embodiments, the NAIONPs lack long-range crystalline order.

[0384] In certain embodiments, the NAIONPs present surface-accessible coordination sites configured to associate with one or more interventional agents.

[0385] In certain embodiments, the interventional agent is reversibly associated with the NAIONPs via coordination chemistry.

[0386] In certain embodiments, the construct is configured to enable functional engagement of the interventional agent in a constrained biological state.

[0387] In certain embodiments, the NAIONPs are configured to modulate one or more of biological stress, exposure kinetics, or cellular interaction context of the interventional agent.

[0388] In certain embodiments, the constrained biological state is defined by a deployment limitation selected from impaired biodistribution, reduced stability, stress sensitivity, altered cellular responsiveness, immune-mediated clearance, or non-optimal functional exposure of the interventional agent when administered in isolation.

[0389] In certain embodiments, the disclosed non-crystalline amorphous iron oxide nanoparticle (NAIONP) compositions are associated with two or more interventional agents configured to address distinct but interrelated aspects of a constrained biological state.

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[0394] In certain embodiments, the one or more interventional agents comprise a glucagon-like peptide-1 (GLP-1) receptor antagonist and a miR-10b-targeting oligonucleotide.

[0395] In such embodiments, the GLP-1 receptor antagonist is configured to modulate systemic or tissue-level pathological conditions associated with oncologic disease, including but not limited to appetite suppression, metabolic dysregulation, endocrine imbalance, or cancer-associated cachexia. The miR-10b-targeting oligonucleotide is configured to inhibit, modulate, or antagonize miR-10b activity in tumor cells or within the tumor microenvironment, including in metastatic or invasive disease states.

[0396] In certain embodiments, the GLP-1 receptor antagonist and the miR-10b-targeting oligonucleotide are simultaneously associated with a single NAIONP dispersion, thereby enabling coordinated deployment of both interventional agents into a constrained biological state.

[0397] In certain embodiments, the GLP-1 receptor antagonist and the miR-10b-targeting oligonucleotide are associated with the NAIONPs via independent association mechanisms, including reversible coordination, covalent attachment, or combinations thereof, such that each interventional agent retains functional availability within the biological system.

[0398] In certain embodiments, the GLP-1 receptor antagonist and the miR-10b-targeting oligonucleotide are co-administered as part of a single NAIONP-associated composition to enable functional engagement in biological contexts where administration of either agent alone is insufficient, poorly tolerated, or deployment-limited.

[0399] In certain embodiments, the combination of a GLP-1 receptor antagonist and a miR-10b-targeting oligonucleotide addresses both systemic pathological constraints and tumor-intrinsic disease drivers, thereby improving the biological context for interventional engagement without requiring direct modification of the molecular identity of either agent.

[0400] In certain embodiments, the NAIONP-associated combination is configured for use in oncologic disease states characterized by metastatic progression, treatment-refractory disease, systemic metabolic stress, or cachexia.

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[0405] Definitions

[0406] As used herein, the term "deployment" refers to the manner, timing, and contextual conditions under which an external biological intervention is introduced to a biological system. Deployment includes, without limitation, physical, chemical, temporal, spatial, and environmental parameters associated with initial exposure, presentation, interaction, or internalization of the intervention. Deployment is distinct from biological function or therapeutic intent in that it concerns how and when an intervention is applied, rather than the biological activity or outcome the intervention is intended to produce.

[0407] As used herein, an "interventional agent" refers to any agent associated with a NAIONP that drives, participates in, enables, supports, or modulates an intervention within a constrained biological state, including an oncologic disease state. Interventional agents include, without limitation, therapeutic agents, targeting agents, affinity ligands, sensitizing agents, stabilizing agents, diagnostic agents, or combinations thereof, whether or not the agent directly exerts a cytotoxic, cytostatic, or disease-modifying effect. As used herein, a "constrained biological state" refers to a biological context—whether in vivo, ex vivo, or in vitro— in which the functional deployment of an interventional agent is limited, distorted, or destabilized by environmental, physiological, treatment-induced, experimental, or system-imposed constraints. Such states may arise from disease, therapeutic intervention, metabolic stress, immune modulation, experimental manipulation, or engineered system conditions, and are not limited to clinically diagnosed disorders.

[0408] Exemplification

[0409] With various embodiments of the invention described above, the following examples are intended to further illustrate and not limit the invention. As used in the Examples herein, a constrained cellular state includes experimentally induced conditions that reduce baseline cell viability or tolerance to exogenous intervention, without requiring a specific disease classification.

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[0414] Example 1 Preparation of Coordination-Stabilized Non-Crystalline Amorphous Iron Oxide Nanoparticles (NAIONP)

[0415] Non-crystalline amorphous iron oxide nanoparticles (NAIONPs) were prepared under fully aqueous, kinetically controlled conditions designed to suppress crystallization and yield a coordination-stabilized colloidal construct suitable for post-synthetic functionalization.

[0416] Materials and Methods

[0417] The nanoparticles were synthesized from aqueous iron and magnesium salts in the presence of citrate, dextran, and a defined set of multidentate coordination ligands. The synthesis was conducted under controlled pH, temperature ramping, and oxidation conditions to arrest particle growth prior to formation of long-range crystalline order. All steps were performed in water without the use of organic solvents, surfactants, or high-energy processing.

[0418] The NAIONPs were stabilized by a multivalent coordination environment comprising: (i) Phosphonate ligands, including ethylphosphonic acid and aminoethylphosphonic acid derivatives, configured to coordinate directly to ferric iron centers and preserve the non-crystalline colloidal structure; (ii) Zwitterionic ligands, including phosphocholine derivatives, configured to promote hydration, charge balance, and resistance to nonspecific adsorption; (iii) Hydrophilic sugar acids, including gluconate and citrate, contributing to colloidal stability, hydration shell formation, and reversible metal-mediated coordination; and (iv) Thiol-reactive ligands, including maleimide-functionalized phosphonate species, providing surface-accessible chemical handles for subsequent association with interventional agents. These ligands were introduced in a staged manner during synthesis to establish a coordination-accessible surface architecture rather than a discrete encapsulating shell.

[0419] SYNTHESIS CONDITIONS. An aqueous reaction mixture containing iron(ll) chloride and magnesium chloride was combined with citrate buffer and dextran under inert conditions. The pH was adjusted to mildly alkaline conditions sufficient to initiate iron oxide formation without inducing rapid precipitation. Controlled introduction of oxygen was used to oxidize iron predominantly to the ferric ( Fe3+) state. The reaction temperature was increased gradually at a rate of less than approximately 1 °C per minute to a moderate elevated temperature and maintained for a defined hold period. Coordination ligands were

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[0424] added during the temperature ramp and hold to arrest particle growth and establish a non-crystalline coordination network. A thiol-reactive ligand was introduced late in the hold period to preserve functional reactivity. Following completion of the temperature hold, the reaction was cooled to room temperature and allowed to undergo a quiescent relaxation period without agitation.

[0425] Results

[0426] The resulting NAIONPs formed a stable, aqueous dispersion without observable aggregation, precipitation, or phase separation. As seen in Figure 1, dynamic light scattering analysis demonstrated a monomodal hydrodynamic size distribution centered at approximately 45 nm. Zeta potential measurements indicated a uniformly anionic surface charge of approximately -27 mV. The particles lacked long-range crystalline order and exhibited reduced magnetic properties relative to crystalline iron oxide nanoparticles. No buffer exchange, filtration, or purification was required to maintain colloidal stability, indicating that stability was intrinsic to the coordination-stabilized construct rather than dependent on encapsulation or polymeric coating.

[0427] STORAGE AND FORMULATION. The NAIONP dispersions were formulated at a defined particle concentration and stored either as aqueous dispersions at refrigerated temperatures or as trehalose- stabilized preparations for frozen or dried storage. In all cases, the nanoparticles retained colloidal integrity and surface accessibility for downstream association with interventional agents.

[0428] UTILITY. The NAIONPs prepared according to this example present surface-accessible coordination and reactive sites suitable for reversible or covalent association with polynucleotides, peptides, proteins, small molecules, targeting moieties, or radiologic agents. The constructs are particularly suited for deployment of interventional agents into constrained biological states where direct administration of such agents is limited by stress sensitivity, tolerability, or impaired functional engagement.

[0429] Example 2 Deployment of siRNA Payloads Using NAIONPs in a Constrained Cellular State

[0430] This example evaluates the ability of non-crystalline amorphous iron oxide nanoparticles (NAIONPs) to enable functional deployment of siRNA payloads under cellular conditions that limit viability, proliferation,

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[0435] or responsiveness when such payloads are administered in isolation. Low-density seeding was used to induce an experimentally tractable constrained cellular state characterized by increased stress sensitivity and reduced baseline survival. Under these conditions, NAIONP-associated siRNA constructs were assessed for their impact on cell viability and population persistence relative to media-only and nonassociated controls.

[0436] HT29 colorectal adenocarcinoma cells were used to evaluate the effects of non-crystalline amorphous iron oxide nanoparticles (NAIONPs), alone or associated with interventional RNA payloads, under low-density seeding conditions that impose cellular stress.

[0437] Materials and Methods

[0438] HT29 and SW480 colorectal adenocarcinoma cells were exposed to non-crystalline amorphous iron oxide nanoparticles (NAIONPs) or NAIONP-siRNA constructs using a single, direct-addition workflow at the time of seeding. No auxiliary transfection reagents, formulation cycling, or media exchange steps were employed. Nanoparticle dispersions were quality-controlled for colloidal stability and size prior to use. Where applicable, siRNA payloads were associated with NAIONPs via thiol-reactive surface chemistry at defined low oligonucleotide loading ratios.

[0439] Following exposure, cells were maintained under low-density plating conditions and analyzed over time using combined nuclear staining and membrane integrity assays. Both adherent and non-adherent cell populations were included in the analysis to capture total population outcomes. Cell viability, morphology, and population distribution were assessed across biologically distinct colorectal cancer cell lines. Statistical analysis was performed using variance-corrected analysis of variance (ANOVA) to evaluate populationlevel effects under stress conditions.

[0440] Results

[0441] Media-only controls and scrambled siRNA conditions exhibited reduced viability relative to seeding controls, consistent with stress-associated loss of early survival under low-density plating conditions.

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[0446] Exposure to NAIONPs in the absence of associated RNA payload was associated with increased cellular viability, indicating mitigation of stress effects independent of payload identity.

[0447] NAIONP-associated siRNA targeting polo-like kinase 1 (siPLK1), delivered at low femtomolar per-cell equivalents, did not induce acute cytotoxicity or widespread growth arrest. Instead, as seen in Figure 2, treated populations exhibited preservation or improvement of viability relative to controls across both HT29 and SW480 cell lines following a single exposure at seeding. These effects persisted over multiple cell divisions, resulting in durable population-level differences at later timepoints. Across all conditions, total cell counts (live plus dead) remained within a comparable range (approximately 1.1 x 105to 1.7 x 105cells), indicating that differences in viability were not attributable to gross differences in seeding density or proliferation during the assay window.

[0448] Interpretation and Relevance to Deployment

[0449] Cellular systems undergoing proliferation behave as exponential populations rather than linear systems. Under such conditions, biological outcomes are determined not only by immediate post-exposure viability, but by the interaction of early survival fraction, division dynamics, and stress tolerance over time. Small differences in early survival can therefore amplify into substantial population-level divergence as cells undergo successive divisions.

[0450] Under biologically constrained conditions— including intracellular delivery stress, mitotic perturbation, metabolic load, or low-density plating— cell populations frequently diverge in behavior. Some subpopulations slow, desynchronize, or fail to re-enter the cell cycle, while more resilient cells maintain near-normal proliferative capacity. As a result, deployment strategies that introduce prolonged stress, repeated formulation steps, or complex optimization workflows may impose cumulative biological penalties that are not evident from short-term viability measurements alone.

[0451] The observations described herein demonstrate that NAIONP-associated delivery enables functional engagement of RNA interventional agents at extremely low input levels while preserving early cellular viability and population fitness under stress. The ability to achieve consistent outcomes across biologically distinct colorectal cancer cell lines without formulation cycling or specialized transfection workflows indicates resilience to biological variability rather than reliance on narrowly optimized delivery conditions.

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[0456] These data support the conclusion that, in constrained biological states, failure of an interventional agent to produce functional outcomes may reflect limitations of deployment rather than intrinsic inactivity. Accordingly, NAIONP-associated constructs enable decoupling of biological execution from molecular identity by modifying the context in which an interventional agent is presented, thereby supporting functional deployment in stressed or fragile biological systems.

[0457] Example 3. Cancer Cachexia treatment effects of a GLP-1 Receptor Antagonist

[0458] This example evaluates the effects of a GLP-1 receptor antagonist (Antagonist 1) in a murine colon-26 tumor model of cancer-associated cachexia. The study assesses body weight and food consumption as functional readouts of systemic metabolic and appetite modulation under tumor-induced stress.

[0459] Materials and Methods

[0460] Cells: Colon-26 cells were obtained from Cell Lines Service (Eppelheim, Germany) and grown in Dulbecco's minimum essential medium supplemented with 10% FBS. Passage 2 was used for this study. To implant the tumor, one million cells were injected subcutaneously on the right flank of mice in a volume of 100 uL PBS.

[0461] Mice: CD2F1 mice (BALB / c x DBA2), males from Charles River Laboratories (Andover, MA), were 11 weeks old at the study start. The study was guided by a protocol approved beforehand by the IACUC.

[0462] Three groups were included in this investigation: age-matched control + vehicle, bid, n = 7, colon-26 tumorbearing + vehicle, bid, n = 5, colon-26 tumor-bearing + Antagonist 1, 3 mg / kg bid, n = 11.

[0463] Treatment: The GLP-1 receptor antagonist VU 0650991, referred to here as Antagonist 1, was obtained from MedChemExpress (Secaucus, NJ). The treatments began on Day 5 post-tumor implantation. The concentration of Antagonist 1 was 0.5 mg / mL, for a dose of 3 mg / kg with each treatment.

[0464] The vehicle was 10% DMSO, 5% Tween 80, 40% PEG 300, 45% PBS. For all treatments, the dose volume was 6 mL / kg, the route was intraperitoneal and the frequency was twice a day (bid).

[0465] Food: The food was standard rodent diet 5001, by PMI Nutrition International (Arden Hills, MN).

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[0470] Statistics: Data are presented as mean ±SD. Groups were compared using ANOVA.

[0471] Results

[0472] Treatment effects of Antagonist 1: The doses of Antagonist 1 were 3 mg / kg bid starting at study day 5 (Figure 3B and 3D), or 5 mg / kg bid starting at study day 11 (Figure 3A and 3C). With the dose administered, there was an initial decline in food intake and loss of body weight, which was regained after a few days of treatment (Figure 3A-D).

[0473] Body weights: Vehicle was well tolerated by the age-matched control group, with body weights on Day 19 post tumor implantation at 102.1 ±0.1% of initial body weights (Figure 3B). The colon-26 mice treated with vehicle lost significant body weight, declining to 81.8 ±6.9% of initial body weights. At study end, the colon-26 mice treated with Antagonist 1 lost less body weight than the vehicle-treated colon-26 group, declining to 90.3 ±4.6% of initial body weights (Figure 3B).

[0474] Food consumption: The colon-26 vehicle-treated group had the lowest food intake, totally 71.5 ±9.3 g per mouse. After an early decline, the colon-26 Antagonist 1-treated group had a consistently higher food intake (Figure 3C, D).

[0475] Inhibition of the GLP-1 receptor likely directly inhibits the appetite suppressing effects of both GLP-1 and insulin. The cachectic tumor itself is derived from the Gl tract. The Gl tract releases several factors that suppress the appetite, including GLP-1. This type of cancer, therefore, may be a source of GLP-1 that induces cachexia directly and, also, indirectly through insulin. Inhibition of the GLP-1 receptor was shown here to cause an increase in food consumption and attenuate muscle loss directly and / or indirectly. This may be of use for the development of a treatment of cancer cachexia. Further research will develop improved pharmacokinetic and pharmacodynamics that result in improved tolerability and support clinical development as a treatment for cancer cachexia.

[0476] Interpretation: Deployment Limitations Reflected by Dosing Stringency

[0477] The dosing regimens required to observe biological effects of Antagonist 1 in this model— specifically, repeated intraperitoneal administration at relatively high milligram-per-kilogram doses and twice-daily

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[0482] frequency— underscore a deployment limitation rather than a lack of intrinsic biological relevance of GLP-1 receptor antagonism. The observed requirement for sustained, frequent dosing reflects the difficulty of achieving durable functional engagement of the interventional agent within a systemically stressed oncologic state.

[0483] In cancer-associated cachexia, the biological environment is characterized by altered metabolism, endocrine disruption, inflammatory signaling, and impaired physiological resilience. Within such a constrained biological state, conventional small-molecule administration may result in rapid clearance, insufficient local exposure, poor tolerability, or transient engagement that necessitates repeated dosing to maintain effect. Accordingly, the necessity for aggressive dosing should be understood as a manifestation of deployment inefficiency rather than an indicator of marginal therapeutic potential. Importantly, the biological outcomes observed in this study— namely, increased food intake and attenuation of body-weight loss despite ongoing tumor burden— demonstrate that modulation of GLP-1 receptor signaling can meaningfully influence systemic pathology. However, the manner in which Antagonist 1 must be administered to achieve these effects highlights a gap between molecular activity and deployable clinical utility. This gap becomes increasingly pronounced in late-stage disease or treatment-stressed systems, where repeated high-dose administration may be impractical, poorly tolerated, or incompatible with concurrent oncologic therapies.

[0484] The compositions disclosed herein address this limitation by enabling association of deployment-limited interventional agents with non-crystalline amorphous iron oxide nanoparticles (NAIONPs), which modify the biological context in which such agents are presented. By altering exposure kinetics, interaction dynamics, and stress coupling— ithout reliance on encapsulation or rigid carrier architectures— NAIONP-associated constructs enable functional engagement of interventional agents at reduced effective doses, with improved tolerability and durability in constrained biological states.

[0485] Accordingly, the relevance of Antagonist 1 in this model lies not in the specific dosing regimen required to observe effect, but in the demonstration that systemic pathological features of oncologic disease are biologically addressable yet deployment-limited. These findings support the use of NAIONP-associated constructs to enable practical deployment of GLP-1 receptor antagonists, alone or in combination with other interventional agents, in cancer-associated cachexia and related systemic disease states.

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[0490] Other Embodiments

[0491] It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

[0492]

Claims

Inventors Docket Number Filing DateD. Bonnin and D. Lazarus PAR-002-PCT January 14, 2026WHAT IS CLAIMED IS:

1. A composition for the deployment of an interventional agent into a constrained biological state, comprising:a. a dispersion of non-crystalline amorphous iron oxide nanoparticles (NAIONPs); and b. one or more interventional agents associated with the NAIONPs.

2. The composition of claim 1, wherein the constrained biological state limits functional deployment of the interventional agent when administered in the absence of the NAIONPs.

3. The composition of claim 1 or 2, wherein the interventional agent is selected from a polynucleotide, peptide, protein, small molecule, targeting moiety, radiologic agent, or a combination thereof.

4. The composition of any one of claims 1-3, wherein the constrained biological state is associated with an oncologic disease selected from primary solid tumors, metastatic disease, hematologic malignancies, or treatment-refractory cancers.

5. The composition of any one of claims 1-4, wherein the constrained biological state comprises a disease-associated systemic condition that limits tolerability or functional deployment of the interventional agent when administered without the NAIONPs.

6. The Composition of claim 5, wherein the interventional agent comprises a glucagon-like peptide- 1 (GLP-1) receptor antagonist, and wherein the composition is configured for deployment in an oncologic disease state.

7. The composition of any one of claims 1-3, wherein the constrained biological state comprises metastatic disease or a metastatic tumor microenvironment.

8. The composition of claim 7, wherein the interventional agent comprises a miR-lOb-targeting oligonucleotide.

9. The composition of claim 1, wherein the one or more interventional agents are comprised of a glucagon-like peptide-1 (GLP-1) receptor antagonist and a miR-10b-targeting oligonucleotide.

10. The composition of any one of claims 1-9, wherein the one or more interventional agents associated with the NAIONPs are independently selected from:a. polynucleotides, including siRNA, antisense oligonucleotides, microRNA inhibitors, microRNA mimics, mRNA, guide RNAs, or combinations thereof;Inventors Docket Number Filing DateD. Bonnin and D. Lazarus PAR-002-PCT January 14, 2026b. peptides or polypeptides, including signaling peptides, antagonists, agonists, enzymes, or fragments thereof;c. proteins, including antibodies, antibody fragments, nanobodies, cytokines, growth factors, or ribonucleoprotein complexes;d. small-molecule agents, including chemotherapeutics, metabolic modulators, sensitizing agents, or pathway inhibitors;e. targeting moieties, including peptides, antibodies, nanobodies, aptamers, affinity ligands, or combinations thereof;f. radiologic agents, including radionuclides, radiotherapeutic agents, radiotracers, or combinations thereof; org. any combination of two or more of (a)- (f).

11. The composition of any one of claims 1-10, wherein the interventional agent is associated with the NAIONPs via reversible coordination, covalent linkage, or a combination thereof.

12. The composition of any one of claims 1-11, wherein two or more interventional agents are associated with a single NAIONP dispersion.

13. The composition of any one of claims 1-11, wherein the interventional agent comprises a radiologic agent selected from a radionuclide, radiotherapeutic moiety, or combination thereof.

14. A method of deploying a deployment-limited interventional agent in a constrained biological state, comprising:a. associating the interventional agent with a non-crystalline amorphous iron oxide nanoparticle (NAIONP) composition; andb. exposing a biological system to the NAIONP composition.

15. The method of claim 14, wherein the biological system comprises a living subject.

16. The method of claim 14, wherein the biological system comprises cultured cells, organoids, tissue explants, or engineered biological constructs.

17. A deployable interventional construct comprising a dispersion of non-crystalline amorphous iron oxide nanoparticles (NAIONPs) synthesized under aqueous, sub-nucleation conditions; wherein the NAIONPs present surface-accessible coordination sites configured to associate with one or more interventional agents; andInventors Docket Number Filing DateD. Bonnin and D. Lazarus PAR-002-PCT January 14, 2026wherein the construct is configured to enable functional engagement of the interventional agent in a constrained biological state.

18. The construct of claim 17, wherein the interventional agent is reversibly associated via coordination chemistry.

19. The construct of claim 17, wherein the NAIONPs are configured to modulate biological stress, exposure kinetics, or cellular interaction context of the interventional agent.

20. The construct of any one of claims 17-19, wherein the constrained biological state is defined by a deployment limitation selected from impaired biodistribution, reduced stability, stress sensitivity, altered cellular responsiveness, immune-mediated clearance, or non-optimal functional exposure of the interventional agent when administered in isolation.Inventors Docket Number Filing DateD. Bonnin and D. Lazarus PAR-002-PCT January 14, 2026REFERENCESU. S. PATENT DOCUMENTSUS 2015 / 0174549 10 / 2023 Lim et alUS 2017 / 0234842 10 / 2014 ReedUS 2023 / 0020016 12 / 2019 Yigit et alUS 9,375,790 10 / 2012 Murphy et alUS 9,629,812 7 / 2011 Medarova et alUS 10,807093 2 / 2016 Belotserkovsky et alOTHER PUBLICATIONSZook, JM et al Stable nanoparticle aggregates / agglomerates of different sizes and the effect of their size on hemolytic cytotoxicity. Nanotoxicology 5:4:517-30 (2011)Vauthier, C et al. How to concentrate nanoparticles and avoid aggregation? 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