Mitochondria-targeted carbon monoxide delivery nanoplatform for enhanced cancer immunotherapy through metabolic-immune reprogramming.

Despite the clinical efficacy of programmed death 1/programmed death ligand 1 (PD-1/PD-L1) blockade therapy, suboptimal patient response rates and unresolved resistance mechanisms remain significant challenges. To address this, we developed a mitochondria-targeted carbon monoxide (CO)-delivering nanoplatform, MnCOTPP/ICG@Cu(tz)@HA (CMIH), designed to disrupt the PD-L1/PD-1 axis through CO-mediated PD-L1 downregulation, thereby augmenting antitumor immunity. The CMIH platform was engineered by co-encapsulating a mitochondria-localized CO donor (MnCOTPP) and the photosensitizer indocyanine green within copper-based metal-organic frameworks (Cu(tz)MOF), followed by hyaluronic acid surface modification for CD44-targeted tumor delivery. Under near-infrared irradiation, mitochondria-localized CO release selectively inhibits cytochrome c oxidase, impairing mitochondrial respiration and alleviating tumor hypoxia. This dual action amplifies singlet oxygen generation to potentiate oxidative stress and immunogenic cell death induction, while concurrently suppressing PD-L1 expression to block immune evasion and reprogram the immunosuppressive tumor microenvironment. Mechanistically, CMIH orchestrates multimodal effects: (1) HIF-1α downregulation, (2) AMPK-mediated PD-L1 degradation, and (3) PD-L1/PD-1 axis blockade. In vivo studies demonstrate that CMIH robustly activates AMPK while suppressing HIF-1α and PD-L1 expression, eliciting potent antitumor immunity and metastasis inhibition. This study introduces a novel CO-based nanotherapeutic strategy that synergistically targets metabolic reprogramming and immune checkpoint blockade, offering a promising solution to overcome current limitations in cancer immunotherapy.