Tumoral/exosomal PD-L1 silencing reinforces mild photothermal therapy by relieving systemic and local immunosuppression

Abstract

Systemic and local immunosuppression dramatically compromises the antitumor efficacy of mild photothermal therapy (mPTT). Herein, a photothermal nanoplatform based on α-helical cationic polypeptide-decorated MoS2 nanosheets (APM) is engineered for PD-L1 siRNA (siPDL1) delivery, which relieves tumoral exosome-mediated systemic immunosuppression and inhibits PD-L1-mediated immune evasion, thus sensitizing the mPTT-induced antitumor immunotherapy. APM is prepared via accelerated ring-opening polymerization (ROP) of N-carboxyanhydride (NCA), and its multivalent structure enables efficient encapsulation of siPDL1 to form the APM@siPDL1 nanocomplexes (NCs) which are further coated with hyaluronic acid (HA) to facilitate tumor targeting. Due to the potent membrane-penetrating capability of the cationic α-helical polypeptide, intravenously injected NCs led to pronounced PD-L1 silencing in both tumor cells and tumor-secreted exosomes, which relieves systemic and local immunosuppression by facilitating the activation, proliferation, and intratumoral infiltration of T lymphocytes and preventing the immune evasion. Subsequent mPTT triggers the immunogenicity enhancement by causing tumor apoptosis and releasing antigens, thus cooperating with siPDL1 to arouse robust antitumor immune response. This study reports a facile method for preparing polypeptide-based hybrid nanomaterials, and it provides an enlightened approach for enhancing the efficacy of antitumor immunotherapy.