Hybrid Membrane-Coated Nanoplatform Enables Pyroptosis-Driven Photothermal Immunotherapy via Synergistic STING/TLR4 Activation

Abstract

The immunosuppressive tumor microenvironment (TME) remains a major barrier to effective cancer immunotherapy, largely due to deficient activation of innate immune pathways and insufficient immune cell infiltration. To address this issue, we developed a hybrid biomimetic nanoplatform (CL8-BO NPs + CLPS) that encapsulates a near-infrared photothermal agent (L8-BO) and the Toll-like receptor 4 (TLR4) agonist lipopolysaccharide, respectively, and is surface-functionalized with a mixed macrophage–red blood cell membrane, with the two components used in synergy. Upon 808 nm laser irradiation, L8-BO generated localized hyperthermia, inducing gasdermin D-dependent pyroptosis, which released cytosolic DNA and damage-associated molecular patterns to activate the stimulator of interferon genes (STING) pathway. Concurrently, released lipopolysaccharide engaged TLR4 signaling, potentiating innate immune activation. In a subcutaneous 4T1 breast carcinoma model, intratumoral administration of CL8-BO NPs followed by laser irradiation remodeled the immunosuppressive TME by promoting dendritic cell maturation, enhancing intratumoral CD8+ cytotoxic T lymphocyte infiltration by 5-fold, and suppressing regulatory T cells and myeloid-derived suppressor cells. The combination therapy inhibits tumor growth by over 90%. This nanoplatform provides a promising strategy for converting “cold” tumors into “hot” tumors through photothermal–triggered pyroptosis and synergistic STING/TLR4 activation in a localized delivery model.