Biodegradable Materials with Disulfide-Bridged-Framework Confine Photosensitizers for Enhanced Photo-Immunotherapy

PURPOSE: Photodynamic therapy (PDT) with spatiotemporal controlled and noninvasive advantages has obtained growing attention in cancer treatment. Nevertheless, PDT still suffers from self-aggregation-induced photosensitizer quenching and reactive oxygen species (ROS) scavenging in cancer cells with abundant glutathione (GSH) pools, leading to insufficient performance. METHODS: In this study, we develop a versatile nanocarrier (SSNs) with a disulfide-bond-bridged silica framework for enhanced photo-immunotherapy. Such SSNs spatially confine photosensitizers Ce6 in the matrix to prevent self-aggregation. Under the high GSH level of cancer cells, the disulfide-bond-bridged framework was degradable and triggered the exposure of photosensitizers to oxygen, accelerating the ROS generation during PDT. In addition, GSH depletion via the break of the disulfide-bond increased the ROS level, together resulting in efficient tumor killing outcomes with a considerable immunogenic cell death effect in vitro. Importantly, the SSNs@Ce6 accumulated in the tumor site and exhibited enhanced PDT efficacy with low systemic toxicity in vivo. RESULTS: The GEN-loaded nanoplatform (Ag-MONs@GEN) showed glutathione-responsive matrix degradation, resulting in the simultaneous controlled release of GEN and silver ions. Ag-MONs@GEN exhibited excellent anti-bacterial activities than Ag-MONs and GEN alone, especially enhancing synergetic effects against four antibiotic-resistant bacteria including Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Enterococcus faecalis. Moreover, Ag-MONs@GEN showed good biocompatibility on L929 and HUVECS. CONCLUSION: Notably, SSNs@Ce6-mediated PDT completely eradicated 4T1 tumors when combined with the PD-1 checkpoint blockade. Overall, the confinement of photosensitizers in a biodegradable disulfide-bridged-framework provides a promising strategy to unleash the potential of photosensitizers in PDT, especially in combined cancer photo-immunotherapy.