Acid-etched layered double hydroxides armed with dual “Doorkeepers” for Immunomodulatory-NIR III photodynamic therapy of hepatocellular carcinoma

Immune checkpoint blockade (ICB) therapy for hepatocellular carcinoma (HCC) is limited due to its immunosuppressive tumor microenvironment (TME). Proinflammatory pyroptosis as a new schedule can induce immunogenic cell death (ICD), thereby reversing immunosuppressive TME and improving ICB efficiency. Herein, we report an acid-etched layered double hydroxides nanosheets (E-LDH)-based smart nanoplatforms armed with H2O2/pH dual "doorkeepers" (denoted as CTEP) targeting HCC to realize membrane-anchored photodynamic therapy (PDT) and evoke potent pyroptosis to effectively improve anti-tumor immunity. The hybrid Hepa1-6 cancer cell membrane (CM) and thylakoid (TK) membrane is cloaked on the surface of pH-(low)-insertion peptide (pHLIP) modified E-LDH to obtain CTEP. Once CTEP nanoplatforms arrive at tumor regions, the dual "doorkeepers" will orderly open to perform PDT precisely. Given the fact that TK membranes have the catalase mimetic function, CTEP is able to respond to high concentrations of H2O2 in TME and rupture the hybrid CM-TK membrane to expose pH-sensitive peptide pHLIP. Membrane-localized PDT can induce gasdermin-D (GSDMD) mediated pyroptosis, effectively stimulating tumor immunogenicity. Pyroptotic cell death releases damage-associated molecular patterns (DAMPs) and consequently robust IaCB ability. CTEP-evoked pyroptosis together with anti-PD-L1 blockade therapy activates adaptive immunity in HCC, successfully inhibiting the progression of primary and distant HCC tumors with mitigation of the side effects. This research has demonstrated that CTEP with excellent biocompatibility and homologous targeting ability can act as a potent pyroptosis inducer to improve immune efficacy. The combination of PDT and immunotherapy via a photo-pyroptosis pathway can be a smart strategy for HCC treatment.