Abstract

Targeted autophagy regulation holds great promise for antitumor therapy, whereas conventional single-modal autophagy interventions easily induce compensatory escape of tumor cells and fail to transform protective autophagy into a lethal phenotype. In this study, a near-infrared (NIR)-responsive polypyrrole/zeolitic imidazolate framework-8 (PPy/ZIF-8) nanoparticle was successfully fabricated. This nanoplatform enables synergistic and precise regulation of autophagic flux, which amplifies upstream autophagy activation and blocks downstream autophagic pathways simultaneously. The incorporation of PPy endows the nanoparticle with excellent near-infrared absorption capability and photothermal effects. It boosts interfacial electron transfer and optimizes electron-hole separation, further enabling the nanoparticles to possess ROS generation ability. Under 808 nm laser irradiation, the generated ROS and zinc ions induce mitochondrial damage to amplify upstream autophagic signals, whereas the photothermal effect impairs lysosomal function and blocks the downstream degradation of autophagosomes. This dual regulatory strategy causes pathological accumulation of autophagosomes and ultimately triggers autophagic cell death in tumor cells. This work validates the feasibility of integrated autophagy regulation and provides a facile and versatile strategy for the design of advanced multimodal antitumor nanotherapeutics.