Defect Engineered Pyroelectric Ca 3 Co 4 O 9− x Nanostructure Enables Pyroptosis and Trained Immunotherapy

ABSTRACT Pyroelectric dynamic therapy is capable of triggering pro‐inflammatory cell death and anti‐tumor trained immunity. However, the high thermal conductivity, quick pyroelectric carrier recombination of traditional pyroelectric materials, and the limited immunogenicity of tumor cells greatly hinder the efficacy of trained immunotherapy. Herein, a nanoplatform integrating iron‐doped defect‐engineered misfit layered calcium cobalt oxide (Ca 3 Co 4 O 9− x ) nanostructure, immune adjuvant polyinosinic‐polycytidylic acid, and nanovesicles extracted from 4T1 cells is constructed to initiate pyroptosis and the anti‐tumor trained immunotherapy. The low thermal conductivity of misfit layered Ca 3 Co 4 O 9− x reduces the overall thermal conductivity. The oxygen vacancies created by defect engineering serve as electron traps, inhibiting charge carrier recombination. Therefore, Ca 3 Co 4 O 9− x achieves multi‐level energy conversion between thermal, electrical, and chemical fields, enriching various reactive oxygen species (ROS). Polyinosinic‐polycytidylic acid synergizing with ROS activates caspase‐1/Gasdermin D‐mediated pyroptosis, and stimulates the secretion of more types of inflammatory cytokines through the stimulator of interferon genes (STING) pathway, leveraging the limited immunogenicity of the tumor environment. Nanovesicles provide precisely homologous tumor‐targeting ability by efficient biomimetic fusion. The nanoplatform demonstrates excellent pyroptosis‐inducing efficiency and anti‐tumor immunity training ability, indicating the feasibility of the multi‐physical field energy conversion and defect engineering strategy for synergistic enhancement of pyroelectric dynamic therapy in anti‐tumor trained immunotherapy.