Oral drug delivery using nano-drug delivery systems (Nano-DDS) faces significant hurdles, primarily due to the inefficient transport across the intestinal mucosa and entry into the bloodstream. Conventional spherical Nano-DDS, while offering stability and symmetry, suffer from limited contact area with bio-interfaces, leading to rapid elimination. The low adhesion between nanoparticles (NPs) and the intestinal mucosa, coupled with inadequate uptake by epithelial cells, significantly hinders the effectiveness of oral Nano-DDS. This study seeks to overcome these limitations by drawing inspiration from viruses, which exhibit exceptional infectivity and tissue/cell penetration capabilities due to their unique morphology, surface topology, and chiral architectures. The high infectivity of viruses stems not only from their nanoscale size and functional capsid proteins, but crucially from their surface topology and chirality, both of which significantly impact their interaction with biological membranes. The nanospikes on viral surfaces provide abundant binding sites, facilitating strong anchoring to biomembranes and enhancing endocytosis. The chiral nature of viruses, driven by the helical structure of their DNA/RNA and the secondary structure of their proteins, further contributes to their high biological activity and interaction specificity. The research aims to design a novel oral Nano-DDS that mimics both the structural and functional aspects of viruses, thereby enhancing oral drug delivery efficiency.

Numerous studies have explored the use of viruses and virus-like particles (VLPs) as nanocarriers for drug and gene delivery. Adenoviruses (ADV) and adeno-associated viruses (AAV) have a long history of clinical development and serve as successful gene delivery platforms for various diseases, including cancer, AIDS, and Alzheimer's disease. Other research has employed hepatitis B core protein (HBC) VLPs to improve the stability of lipophilic near-infrared dyes, and peptidyl VLPs mimicking the human immunodeficiency virus (HIV) have been shown to deliver CRISPR/Cas9 systems effectively. The rabies virus has also inspired the design of silica-coated gold nanorods for brain glioma treatment. These examples highlight the potential of virus-mimicking strategies, but further research is needed to translate these concepts into efficient and safe oral drug delivery systems. This research emphasizes the importance of not only mimicking the size and capsid protein of viruses but also their intricate surface topology and chirality, which play critical roles in their interaction with and penetration of biological barriers. The overall aim is to bridge the gap between virus-inspired designs and clinically translatable oral drug delivery systems.

The research employed a multi-step approach to synthesize and characterize core-shell mesoporous silica nanoparticles with virus-like nanospikes (VSN) and subsequent modification with L-alanine (CVSN). Initially, mesoporous silica NPs with spiky surfaces (VSN) were created using a single-micelle epitaxial growth strategy, optimizing surfactant concentration for controlled interfacial growth. Chirality was introduced by modifying VSN with L-alanine (CVSN) via amination and acylation. The synthesized nanoparticles (SSN, MSN, VSN, and CVSN) were characterized using various techniques, including FTIR, TEM, SEM, AFM, XPS, TGA, SAXS, and N2 adsorption/desorption analysis. Their surface properties were evaluated through determination of surface hydroxyl density, wettability (contact angle measurements), oil-water partition coefficients, amino acid adsorption capacity, and degradation behavior in simulated physiological fluids (SGF, SIF, SBF). The nanoparticles' ability to penetrate intestinal mucus (both rat and human) was assessed using 3D confocal laser scanning microscopy (CLSM) and quantitative analysis of permeation ratios. Bio-adhesion and retention in the gastrointestinal (GI) tract were evaluated through an elution method with both rat and human intestinal mucosa, and in vivo studies utilizing the IVIS Lumina imaging system. Cellular uptake mechanisms in Caco-2 cells were explored using CLSM, flow cytometry (FCM), and bio-TEM. In vitro and in vivo biocompatibility tests included CCK-8 assays, hemolysis tests, protein adsorption assays, hematological and biochemical analyses, and histopathological examinations in mice. For drug loading, indomethacin (IMC) was encapsulated into the mesoporous nanoparticles (MSN, VSN, CVSN) using a solvent evaporation method and characterized by FTIR, XRD, and DSC. In vitro drug release was assessed in different pH conditions, followed by ex vivo and in vivo studies evaluating pharmacokinetics, biodistribution, and pharmacodynamics using everted intestinal sacs, pharmacokinetic analysis, mouse ankle swelling test (MAST), mouse ear swelling test (MEST), and mouse writhing test (MWT). The versatility of CVSN as an oral Nano-DDS was evaluated by loading a series of NSAIDs with diverse physicochemical properties, followed by in vitro and in vivo studies assessing their intestinal transport and therapeutic efficacy.

The study successfully synthesized CVSN nanoparticles with a virus-mimicking surface topology and chiral properties. Characterizations revealed uniform mesopores, abundant functional groups, strong wettability, and chiral recognition ability. CVSN exhibited significantly enhanced penetration through intestinal mucus compared to control nanoparticles (SSN, MSN, VSN), as evidenced by 3D CLSM imaging and quantitative permeation analysis. Bio-adhesion studies demonstrated that CVSN exhibited superior adhesion to both rat and human intestinal mucosa compared to SSN, MSN, and VSN due to multi-site anchoring and chiral recognition. In vivo studies showed that CVSN had a significantly longer retention time in the GI tract. The absorption of CVSN through the intestinal villi was significantly enhanced compared to the control nanoparticles, as observed by CLSM and bio-TEM. Competitive absorption studies further confirmed the superior oral adsorption of CVSN. In Caco-2 cells, CVSN showed significantly higher cellular uptake than the control NPs via multiple endocytic pathways, with significant contribution from macropinocytosis. Biocompatibility studies indicated negligible toxicity and good hemocompatibility of the nanoparticles both in vitro and in vivo. When indomethacin (IMC) was loaded into CVSN, the resulting Nano-DDS showed improved drug loading, enhanced drug release, dramatically increased oral bioavailability, and superior anti-inflammatory efficacy in MAST and MEST models compared to free IMC and IMC loaded in other NPs. Finally, a panel of NSAIDs with various physicochemical properties demonstrated the versatility of CVSN as a platform for oral drug delivery, showing consistent improvement in intestinal transport and therapeutic effect compared to their free drug forms.

This research successfully demonstrates the potential of a virus-mimicking strategy for significantly enhancing the oral bioavailability of poorly soluble and/or poorly permeable drugs. The enhanced performance of CVSN nanoparticles can be attributed to their unique combination of virus-like surface topology and chirality. The spiky surface provides multiple binding sites for interacting with the intestinal mucosa and facilitates penetration of the mucus layer. Chiral recognition further enhances the interaction with membrane proteins, promoting cellular uptake. The results have significant implications for drug delivery, offering a novel approach to overcome the challenges associated with oral administration of various therapeutic agents. The successful application of CVSN to a range of NSAIDs further strengthens the versatility of this platform. The findings suggest that incorporating the key features of viral morphology and chirality into nanocarrier design can greatly improve drug delivery efficiency, opening new avenues for the development of advanced oral drug delivery systems.

This study presents a novel virus-mimicking strategy for designing oral Nano-DDS using core-shell mesoporous silica nanoparticles with virus-like nanospikes modified with L-alanine (CVSN). CVSN exhibits significantly enhanced oral bioavailability compared to control nanoparticles and dramatically improves the efficacy of multiple NSAIDs. The results highlight the importance of surface topology and chirality in designing efficient nanocarriers for oral drug delivery, opening up new possibilities for improving the treatment of various diseases. Future research could explore the application of CVSN to other drug classes and optimize the design for improved efficacy and safety.

While the study provides compelling evidence for the efficacy of CVSN nanoparticles, some limitations exist. The in vivo studies were primarily conducted in mice, and further research in larger animal models is necessary to confirm the findings' generalizability to humans. Long-term toxicity studies are also needed to fully assess the safety profile of CVSN. Furthermore, the exact mechanisms of interaction between CVSN and the intestinal barrier warrant further investigation. The study mainly focuses on NSAIDs; thus, broader applicability across various drug types needs further exploration.