Asymmetric mesoporous silica nanoparticles (MSNs) with controllable head-tail structures have been successfully synthesized. The head particle type is tunable (solid or porous), and the tail has dendritic large pores. The tail length and tail coverage on head particles are adjustable. Compared to spherical silica nanoparticles with a solid structure (Stöber spheres) or large-pore symmetrical MSNs with fully covered tails, asymmetrical head-tail MSNs (HTMSNs) show superior hemocompatibility due to reduced membrane deformation of red blood cells and decreased level of reactive oxygen species. Moreover, compared to Stöber spheres, asymmetrical HTMSNs exhibit a higher level of uptake and in vitro maturation of immune cells including dendritic cells and macrophage. This study has provided a new family of nanocarriers with potential applications in vaccine development and immunotherapy.

Hypoxia-activated prodrugs have brought new opportunities for safe and effective tumor ablation, but their therapeutic efficacy is limited by insufficient activation in tumor microenvironments. Herein, a novel cascade delivery system with tandem functions by integrating a hypoxia-activated prodrug (AQ4N) and glucose oxidase (GOx) is designed to improve its efficacy. Innovative yolk-shell organosilica nanoparticles with a tetrasulfide bridged composition, a small-pore yolk, and a large-pore shell featuring a shell-to-yolk stepwise degradability are constructed as a carrier for AQ4N and GOx, one enzyme that catalyzes the oxidation of glucose to produce hydrogen peroxide. The glutathione (GSH) is depleted by tetrasulfide bond in the framework and induces shell degradation for fast release of GOx, which in turn induces starvation (glucose removal), oxidative cytotoxicity (H 2 O 2 production and GSH depletion), and hypoxia (oxygen consumption). Finally, the hypoxia activates the liberated prodrug AQ4N for chemotherapy. The cascading and synergistic functions including GSH depletion, starvation, oxidative cytotoxicity, and chemotherapy lead to improved performance in tumor inhibition and antimetastasis.

Immunosuppressive tumors generally exhibit poor response to immune checkpoint blockade based cancer immunotherapy. Rationally designed hybrid nanoreactors are now presented that have integrated functions as Fenton catalysts and glutathione depletion agents for amplifying the immunogenic cell death and activating immune cells. A simple physical mixture of nanoreactors and chemodrugs in combination with immune checkpoint blockades show synergistically and concurrently enhanced chemo-immunotherapy efficacy, inhibiting the growth of both treated primary immunosuppressive tumors and untreated distant tumors. The off-the-shelf strategy uses tumor antigens generated in situ and avoids cargo loading, and is thus a substantial advance in personalized nanomedicine for clinical translation.

An urgent demand exists for the development of effective carrier systems that systematically enhance the cellular uptake and localization of antibiotic drugs for the treatment of intracellular pathogens. Commercially available antibiotics suffer from poor cellular penetration, restricting their efficacy against pathogens hosted and protected within phagocytic cells. In this study, the potency of the antibiotic rifampicin against intracellular small colony variants of Staphylococcus aureus was improved through encapsulation within a strategically engineered cellpenetrant delivery system, composed of lipid nanoparticles encapsulated within a poly(lactic-co-glycolic) acid (PLGA) nanoparticle matrix. PLGA−lipid hybrid (PLH) microparticles were synthesized through the process of spray drying, whereby rifampicin was loaded within both the polymer and lipid phases, to create a nanoparticle-in-microparticle system capable of efficient redispersion in aqueous biorelevant media and with programmable release kinetics. The ability of PLH particles to disintegrate into nanoscale agglomerates of the precursor nanoparticles was shown to be instrumental in optimizing rifampicin uptake in RAW264.7 macrophages, with a 7.2-and 1.6-fold increase in cellular uptake, when compared to the pure drug and PLGA microparticles (of an equivalent initial particle size), respectively. The enhanced phagocytosis and extended drug release mechanism (under the acidic macrophage environment) associated with PLH particles induced a 2.5-log reduction in colony forming units compared to initial colonies at 2.50 μg/mL rifampicin dose. Thus, the ability of PLH particles to reduce the intracellular viability of S. aureus, without demonstrating significant cellular toxicity, satisfies the requirements necessary for the safe and efficacious delivery of antibiotics to macrophages for the treatment of intracellular infections.

Mesoporous silica nanoparticles are reported as adjuvants in nanovaccines in generating robust antigen-specific immunity. However, the effect of surface chemistry in initiating and modulating the immune response remains largely unexplored. In this study, mesoporous silica nanorods (MSNRs) are modified with NH and C groups to investigate the influence of surface functional groups (OH, NH , and C ) on their adjuvant efficacy. It is found that compared to OH and NH groups, the hydrophobic C modification significantly enhances antigen uptake by antigen presenting cells and endosomal-lysosomal escape in vitro, dendritic cells, and macrophages maturation ex vivo, and elicits secretion of interferon-γ level and antibody response in immunized mice. Moreover, bare MSNR and MSNRNH exhibit T-helper 2 biased immune response, while MSNRC shows a T-helper 1 biased immune response. These findings suggest that the surface chemistry of nanostructured adjuvants has profound impact on the immune response, which provides useful guidance for the design of effective nanomaterial based vaccines.

Asymmetric mesoporous silica nanoparticles with a head-tail structure are potent immunoadjuvants for delivering a peptide antigen, generating a higher antibody immune response in mice compared to their symmetric counterparts.

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Benzene-bridged dendritic mesoporous organosilica nanoparticles significantly improve the catalytic activity and stability of lipase.