This review focuses on the surface modification of metallic nanoparticles for targeted drug delivery. Metallic nanoparticles, owing to their unique size, stability, and payload capacity, have emerged as promising drug carriers. However, their application necessitates surface modification to enable precise targeting. Various strategies, such as polymer coating methods, the use of functional groups, and bio-conjugation with targeting ligands, are explored. The review also discusses the selection of ligands based on target receptors, active and passive targeting approaches, and stimuli-responsive targeting. It further delves into the challenges of translating these strategies to clinical settings, including scalability, toxicity, and regulatory hurdles. The surface modification of metallic nanoparticles is a promising avenue for targeted drug delivery. Various strategies, including polymer coating, functionalization with specific groups, and bioconjugation with targeting ligands, have been explored to enhance the therapeutic potential of these nanoparticles. The challenges in clinical translation, continuous advancements in nanoparticle synthesis, and surface modification techniques offer a positive outlook for the future of targeted metallic nanoparticle systems. Despite the promising potential of metallic nanoparticles in drug delivery, there are several challenges that need to be addressed for their successful clinical translation. These include scalable fabrication and functionalization of nanoparticles, toxicity concerns, and regulatory hurdles. However, continuous advancements in nanoparticle synthesis and surface modification techniques are expected to overcome these challenges in the near future.

Surface Modification of Metallic Nanoparticles for Targeting Drugs

Bioorthogonal catalysis (BC) generates chemical reactions not present in normal physiology for the purpose of disease treatment. Because BC catalytically produces the desired therapy only at the site of disease, it holds the promise of site-specific treatment with little or no systemic exposure or side effects. Transition metals are typically used as catalytic centers in BC; however, solubility and substrate specificity typically necessitate a coordinating enzyme and/or stabilizing superstructure for in vivo application. We report the use of self-assembling, porous exoshells (tESs) to encapsulate and deliver an iron-containing reaction center for the treatment of breast cancer. The catalytic center is paired with indole-3-acetic acid (IAA), a natural product found in edible plants, which undergoes oxidative decarboxylation, via reduction of iron(III) to iron(II), to produce free radicals and bioactive metabolites. The tES encapsulation is critical for endocytic uptake of BC reaction centers and, when followed by administration of IAA, results in apoptosis of MDA-MB-231 triple negative cancer cells and complete regression of in vivo orthotopic xenograft tumors (p < 0.001, n = 8 per group). When Renilla luciferase (rLuc) is substituted for horseradish peroxidase (HRP), whole animal luminometry can be used to monitor in vivo activity.

Bioorthogonal Catalysis for Treatment of Solid Tumors Using Thermostable, Self-Assembling, Single Enzyme Nanoparticles and Natural Product Conversion with Indole-3-acetic Acid

Antigen delivery based on non-virus-like particle self-associating protein nanoscffolds, such as Aquifex aeolicus lumazine synthase (AaLS), is limited due to the immunotoxicity and/or premature clearance of antigen-scaffold complex resulted from triggering unregulated innate immune responses. Here, using rational immunoinformatics prediction and computational modeling, we screen the T epitope peptides from thermophilic nanoproteins with the same spatial structure as hyperthermophilic icosahedral AaLS, and reassemble them into a novel thermostable self-assembling nanoscaffold RPT that can specifically activate T cell-mediated immunity. Tumor model antigen ovalbumin T epitopes and the severe acute respiratory syndrome coronavirus 2 receptor-binding domain are loaded onto the scaffold surface through the SpyCather/SpyTag system to construct nanovaccines. Compared to AaLS, RPT -constructed nanovaccines elicit more potent cytotoxic T cell and CD4+ T helper 1 (Th1)-biased immune responses, and generate less anti-scaffold antibody. Moreover, RPT significantly upregulate the expression of transcription factors and cytokines related to the differentiation of type-1 conventional dendritic cells, promoting the cross-presentation of antigens to CD8+ T cells and Th1 polarization of CD4+ T cells. RPT confers antigens with increased stability against heating, freeze-thawing, and lyophilization with almost no antigenicity loss. This novel nanoscaffold offers a simple, safe, and robust strategy for boosting T-cell immunity-dependent vaccine development.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/advs.202303049

T Cell Activating Thermostable Self-Assembly Nanoscaffold Tailored for Cellular Immunity Antigen Delivery.

Thermostable exoshells (tES) are engineered proteinaceous nanoparticles used for the rapid encapsulation of therapeutic proteins/enzymes, whereby the nanoplatform protects the payload from proteases and other denaturants. Given the significance of oral delivery as the preferred model for drug administration, we structurally improved the stability of tES through multiple inter-subunit disulfide linkages that were initially absent in the parent molecule. The disulfide-linked tES, as compared to tES, significantly stabilized the activity of encapsulated horseradish peroxidase (HRP) at acidic pH and against the primary human digestive enzymes, pepsin, and trypsin. Furthermore, the disulfide-linked tES (DS-tES) exhibited significant intestinal permeability as evaluated using Caco2 cells. In vivo bioluminescence assay showed that encapsulated Renilla luciferase (rluc) was ~3 times more stable in mice compared to the free enzyme. DS-tES collected mice feces had ~100 times more active enzyme in comparison to the control (free enzyme) after 24 h of oral administration, demonstrating strong intestinal stability. Taken together, the in vitro and in vivo results demonstrate the potential of DS-tES for intraluminal and systemic oral drug delivery applications.

/pdf/gastrointestinal-tract-stabilized-protein-delivery-using-2vc2uavu.pdf

Gastrointestinal Tract Stabilized Protein Delivery Using Disulfide Thermostable Exoshell System

New insights into the treatment of polycystic ovary syndrome: HKDC1 promotes the growth of ovarian granulocyte cells by regulating mitochondrial function and glycolysis.

Protein macromolecules occur naturally at the nanoscale. The use of a dedicated nanoparticle as a lyophilization excipient, however, has not been reported. Because biopolymeric and lipid nanoparticles often denature protein macromolecules and commonly lack the structural rigidity to survive the freeze-drying process, we hypothesized that surrounding an individual protein substrate with a nanoscale, thermostable exoshell (tES) would prevent aggregation and protect the substrate from denaturation during freezing, sublimation, and storage. We systematically investigated the properties of tES, including secondary structure and its homogeneity, throughout the process of lyophilization and found that tES have a near 100% recovery following aqueous reconstitution. We then tested the hypothesis that tES could encapsulate a model substrate, horseradish peroxidase (HRP), using charge complementation and pH-mediated controlled assembly. HRP were encapsulated within the 8 nm internal tES aqueous cavity using a simplified loading procedure. Time-course experiments demonstrated that unprotected HRP loses 95% of activity after 1 month of lyophilized storage. After encapsulation within tES nanoparticles, 70% of HRP activity was recovered, representing a 14-fold improvement and this effect was reproducible across a range of storage temperatures. To our knowledge, these results represent the first reported use of nanoparticle encapsulation to stabilize a functional macromolecule during lyophilization. Thermostable nanoencapsulation may be a useful method for the long-term storage of labile proteins.

Nanoencapsulation as a General Solution for Lyophilization of Labile Substrates

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Nanoencapsulation as a General Solution for Lyophilization of Labile Substrates

Gastrointestinal Tract Stabilized Protein Delivery Using Disulfide Thermostable Exoshell System