Cleavage of Homonuclear Chalcogen-Chalcogen Bonds in a Hybrid Platform in Response to X-ray Radiation Potentiates Tumor Radiochemotherapy.

Chalcogens are used as sensitive redox-responsive reagents in tumor therapy. However, chalcogen bonds triggered by external ionizing radiation, rather than by internal environmental stimuli, enable site-directed and real-time drug degradation in target lesions. This approach helps to bypass chemoresistance and global systemic toxicity, presenting a significant advancement over traditional chemoradiotherapy. In this study, we fabricated a hybrid monodisperse organosilica nanoprodrug based on homonuclear single bonds (disulfide bonds (S-S, approximately 240 kJ/mol), diselenium bonds (Se-Se, approximately 172 kJ/mol), and tellurium bonds (Te-Te, 126 kJ/mol)), including ditelluride-bond-bridged MONs (DTeMSNs), diselenide-bond-bridged MONs (DSeMSNs) and disulfide-bond-bridged MONs (DSMSNs). The results demonstrated that differences in electronegativities and atomic radii influenced their oxidation sensitivities and reactivities. Tellurium, with the lowest electronegativity, showed the highest sensitivity, followed by selenium and sulfur. DTeMSNs exhibited highly responsive cleavage upon exposure to X-rays, resulting in oxidation to TeO32-. Furthermore, chalcogen-hybridized organosilica was loaded with manganese ions (Mn2+) to enhance the release of Mn2+ during radiotherapy, thereby activating the the stimulator of interferon genes (STING) pathway and enhancing the tumor immune response to inhibit tumor growth. This investigation of hybrid organosilica deepens our understanding of chalcogens response characteristics to radiotherapy and enriches the design principles for nanomedicine based on prodrugs.

Surface chemistry engineered selenium nanoparticles as bactericidal and immuno-modulating dual-functional agents for combating methicillin-resistant Staphylococcus aureus Infection.

Because of the extremely complexed microenvironment of drug-resistant bacterial infection, nanomaterials with both bactericidal and immuno-modulating activities are undoubtedly the ideal modality for overcoming drug resistance. Herein, we precisely engineered the surface chemistry of selenium nanoparticles (SeNPs) using neutral (polyvinylpyrrolidone-PVP), anionic (letinan-LET) and cationic (chitosan-CS) surfactants. It was found that surface chemistry greatly influenced the bioactivities of functionalized SeNPs, their interactions with methicillin-resistant Staphylococcus aureus (MRSA), immune cells and metabolisms. LET-functionalized SeNPs with distinct metabolisms exhibited the best inhibitory efficacy compared to other kinds of SeNPs against MRSA through inducing robust ROS generation and damaging bacterial cell wall. Meanwhile, only LET-SeNPs could effectively activate natural kill (NK) cells, and enhance the phagocytic capability of macrophages and its killing activity against bacteria. Furthermore, in vivo studies suggested that LET-SeNPs treatment highly effectively combated MRSA infection and promoted wound healing by triggering much more mouse NK cells, CD8+ and CD4+ T lymphocytes infiltrating into the infected area at the early stage to efficiently eliminate MRSA in the mouse model. This study demonstrates that the novel functionalized SeNP with dual functions could serve as an effective antibacterial agent and could guide the development of next generation antibacterial agents.

Oral Hydrogel Microbeads-Mediated In Situ Synthesis of Selenoproteins for Regulating Intestinal Immunity and Microbiota.

Selenoprotein plays a crucial role in immune cells and inflammatory regulation. However, as a protein drug that is easily denatured or degraded in the acidic environment of the stomach, efficient oral delivery of selenoprotein is a great challenge. Herein, we innovated an oral hydrogel microbeads-based biochemical strategy that can in situ synthesize selenoproteins, therefore bypassing the necessity and harsh conditions for oral protein delivery while effectively generating selenoproteins for therapeutic applications. The hydrogel microbeads were synthesized by coating hyaluronic acid-modified selenium nanoparticles with a protective shell of calcium alginate (SA) hydrogel. We tested this strategy in mice with inflammatory bowel disease (IBD), one of the most representative diseases related to intestinal immunity and microbiota. Our results revealed that hydrogel microbeads-mediated in situ synthesis of selenoproteins could prominently reduce proinflammatory cytokines secretion and mediate immune cells (e.g., reduce neutrophils and monocytes and increase immune regulatory T cells) to effectively relieve colitis-associated symptoms. This strategy was also able to regulate gut microbiota composition (increase probiotics abundance and suppress detrimental communities) to maintain intestinal homeostasis. Considering intestinal immunity and microbiota widely associated with cancers, infections, inflammations, etc., this in situ selenoprotein synthesis strategy might also be possibly applied to broadly tackle various diseases.

A facile and general method for synthesis of antibiotic-free protein-based hydrogel: Wound dressing for the eradication of drug-resistant bacteria and biofilms.

Antibacterial protein hydrogels are receiving increasing attention in the aspect of bacteria-infected-wound healing. However, bacterial drug resistance and biofilm infections lead to hard healing of wounds, thus the construction of biological agents that can overcome these issues is essential. Here, a simple and universal method to construct antibiotic-free protein hydrogel with excellent biocompatibility and superior antibacterial activity against drug-resistant bacteria and biofilms was developed. The green industrial microbicide tetrakis (hydroxymethyl) phosphonium sulfate (THPS) as cross-linking agent can be quickly cross-linked with model protein bovine serum albumin (BSA) to form antibacterial hydrogel through simple mixing without any other initiators, subsequently promoting drug-resistance bacteria-infected wound healing. This simple gelatinization strategy allows at least ten different proteins to form hydrogels (e.g. BSA, human serum albumin (HSA), egg albumin, chymotrypsin, trypsin, lysozyme, transferrin, myohemoglobin, hemoglobin, and phycocyanin) under the same conditions, showing prominent universality. Furthermore, drug-resistance bacteria and biofilm could be efficiently destroyed by the representative BSA hydrogel (B-Hydrogel) with antibacterial activity, overcoming biofilm-induced bacterial resistance. The in vivo study demonstrated that the B-Hydrogel as wound dressing can promote reepithelization to accelerate the healing of methicillin-resistant staphylococcus aureus (MRSA)-infected skin wounds without inducing significant side-effect. This readily accessible antibiotic-free protein-based hydrogel not only opens an avenue to provide a facile, feasible and general gelation strategy, but also exhibits promising application in hospital and community MRSA disinfection and treatment.