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/MnO 2 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 MnO 2 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-1α expression and increased immune-activated cell infiltration were also observed in RKCM /laser treatment xenograft. Mechanically, (1) Ce6 can induce singlet oxygen ( 1 O 2 ) generation under laser irradiation to give photodynamic therapy (PDT); (2) MnO 2 can react with H 2 O 2 in situ to supply additional O 2 to alleviate tumor hypoxia; and (3) the released Mn 2+ ions can induce a Fenton-like reaction to generate • 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/MnO 2 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.