The redox homeostasis-reshapable hyaluronic acid-drug conjugate augments chemo-photodynamic therapy

The tumor microenvironment poses significant challenges to reactive oxygen species treatment, and fails to retain small molecule drugs for extended periods, leading to low treatment efficacy. Here, a hyaluronic acid-based nanoplatform (HCCD) for combined chemotherapy and photodynamic therapy (PDT) is developed. The nanoplatform links chlorin e6 (Ce6) and doxorubicin (DOX) with hyaluronic acid through a glutathione (GSH)-sensitive disulfide bond, resulting their fluorescence quenching. Notably, their fluorescence and cytotoxicity are specifically activated in tumor cells, not normal ones, due to the endogenous GSH-mediated cleavage of disulfide bonds. Furthermore, PDT is activated in tumor cells with 660 nm laser, and GSH consumption reshapes redox homeostasis balance, thereby synergistically enhancing the anti-tumor efficacy with chemotherapy. HCCD predominantly accumulates in tumors in vivo, enabling precise localization and guidance for PDT and chemotherapy. This approach results in a significant reduction in tumor size, by a factor of 11 compared to the control group, with tumors nearly disappearing. Additionally, HCCD with the toll-like receptor 7 agonist imiquimod (R837) and anti-programmed death ligand 1 (anti-PD-L1) activated systemic immune response, suppressing distant tumor growth. Therefore, it's a promising strategy for precise tumor targeting and combination therapy, with potential in immunotherapy to inhibit primary and metastatic tumor growth.