Mitochondria–Neutrophil Hybrid Membrane Nanovesicles for Photo-Driven Calcium Overload and Suppression of Phototherapy-Evoked Inflammation and Metastasis

Phototherapy holds great potential for localized tumor treatment but is limited by sublethal stress-induced thermal resistance, therapy-triggered inflammatory amplification, myeloid-derived suppressor cell (MDSC) infiltration, and subsequent distant metastasis. In this study, we fabricated mitochondria–neutrophil hybrid membrane-coated nanovesicles (MN iCa NPs) co-loaded with a pH-responsive calcium phosphate (CaP) core and indocyanine green (ICG) to achieve photoactivated mitochondrial Ca 2+ overload together with anti-inflammatory and antimetastatic effects. The neutrophil membrane provides the nanosystem with inflammatory tumor targeting, pro-inflammatory cytokine and chemokine sequestration, reduced MDSC accumulation, and inhibition of tumor–neutrophil crosstalk to suppress metastasis, whereas the mitochondrial membrane facilitates organelle-specific delivery. Upon 808-nm laser irradiation, photostress-induced mitochondrial matrix acidification promotes in situ CaP dissolution, initiating a predominantly MCU-independent intramitochondrial Ca 2+ burst, while mitochondrial calcium uniporter (MCU)-mediated Ca 2+ influx further amplifies mitochondrial Ca 2+ accumulation and downstream injury. This locally initiated and subsequently amplified Ca 2+ overload leads to irreversible mitochondrial dysfunction, ATP depletion, and apoptosis, thereby overcoming thermal resistance. In 4T1 breast cancer models, MN iCa NPs exhibited excellent tumor ablation efficacy, with the apoptosis rate increased by 53.45% and tumor weight reduced by 90.36% compared with free ICG, while also alleviating inflammation and MDSC accumulation, and nearly eliminating lung metastasis without obvious systemic toxicity. This biomimetic nanoplatform integrates organelle-specific Ca 2+ overload with immunomodulatory and antimetastatic functions, providing a promising strategy for overcoming the key limitations of conventional phototherapy.