Near-infrared light-controlled multimodal mitochondria therapy overcomes triple‑negative breast cancer

Targeting mitochondria offers a powerful strategy against aggressive cancers like triple negative breast cancer (TNBC), yet achieving synergistic, multimodal therapeutic effects remains a formidable challenge. The primary hurdle is the lack of precise spatiotemporal control over these combined modalities, often resulting in systemic toxicity and compromised efficacy. Here, we develop a near-infrared (NIR)-light-gated nanoplatform that places a triple-pronged mitochondrial assault under precise photonic command. Central to our design, NIR-excited upconversion nanoparticles activate an embedded photo-acid generator (o-nitrobenzaldehyde, o-NBA) to create a rapid, localized acidic spike within the tumor microenvironment. This single acid-trigger simultaneously drives the decomposition of iron disulfide, releasing Fe^{2 +} for potent chemodynamic therapy and hydrogen disulfide (H₂S₂) as an intermediate. The H₂S₂ then reacts with glutathione (GSH) to generate hydrogen sulfide (H₂S), which critically sensitizes cancer cells to ferroptosis by depleting GSH and inhibiting catalase (CAT). At the same time, the acidic milieu facilitates the controlled release of Lapatinib (Lp) to induce mitochondrial structural collapse and apoptosis. This orchestrated triple-blow, converging on the mitochondrial matrix, demonstrates exceptional antitumor efficacy in both in vitro and in vivo models, presenting a potent paradigm for stimuli-responsive, precision therapy against TNBC.