Cancer-Responsive Multifunctional Nanoplatform Based on Peptide Self-Assembly for Highly Efficient Combined Cancer Therapy by Alleviating Hypoxia and Improving the Immunosuppressive Microenvironment

Hypoxia, as a main feature of the tumor microenvironment, has greatly limited the efficacy of photodynamic therapy (PDT), as well as its clinical application. Here, a multifunctional composite nanoplatform, the peptide/Ce6/MnO2 nanocomposite (RKCM), has been constructed to alleviate tumor hypoxia and increase the efficacy of PDT using rationally designed peptide fibrils to encapsulate chlorin e6 (Ce6) inside and to mineralize MnO2 nanoparticles on the surface. As a result, RKCM significantly improved the PDT efficacy by increasing reactive oxygen species (ROS) generation, decreasing tumor cell viability, and inhibiting tumor growth and metastasis. Besides, decreased HIF-1 alpha expression and increased immune-activated cell infiltration were also observed in RKCM/laser treatment xenograft. Mechanically, (1) Ce6 can induce singlet oxygen (1O2) generation under laser irradiation to give photodynamic therapy (PDT); (2) MnO2 can react with H2O2 in situ to supply additional O2 to alleviate tumor hypoxia; and (3) the released Mn2+ ions can induce a Fenton-like reaction to generate center dot OH for chemical dynamic therapy (CDT). Moreover, RKCM/laser treatment also presented with an abscopal effect to block the occurrence of lung metastasis by remolding the pre-metastasis immune microenvironment. With these several aspects working together, the peptide/Ce6/MnO2 nanoplatform can achieve highly efficient tumor therapy. Such a strategy based on peptide self-assembly provides a promising way to rationally design a cancer-responsive multifunctional nanoplatform for highly efficient combined cancer therapy by alleviating hypoxia and improving the immune microenvironment.