Near‐Infrared Upconversion Modulation of Intracellular Protons for Autophagy‐Induced Apoptosis

ABSTRACT Protons critically regulate cancer cell behavior, metabolism, and signaling pathways, making intracellular pH modulation a promising therapeutic strategy. Yet, precise spatiotemporal control of proton levels remains a formidable challenge. In this study, we introduce a near‐infrared (NIR)‐controlled nanoscale proton delivery system using upconversion nanoparticles (UCNPs) coated with photoacid (PA) and ferrocene (Fc). Upon 980 nm NIR stimulation, UCNPs emit UV–visible emission (300–500 nm), activating surface‐bound PA to induce transient H + release and acidify the tumor microenvironment in vivo. This acute acidic stress reduces tumor cell glucose uptake by 50% and suppresses mechanistic target of rapamycin (mTOR) signaling, triggering excessive autophagy that functionally drives mitochondrial dysfunction and intrinsic apoptosis—a process we define as proton‐mediated autophagy‐induced apoptosis (PAA). Fc, a biodegradable peroxidase mimic and a non‐fluorescent quencher, is incorporated to enable real‐time visual quantification of proton accumulation via H + ‐triggered biodegradation, restoring the NIR upconversion luminescence (at 800 nm) of UCNPs. Following intravenous administration, the nanoagent achieves a six‐fold reduction in tumor weight and elevates proton levels in glioma, effectively triggering PAA under non‐invasive NIR irradiation. This work establishes a spatiotemporally controlled platform for intratumoral proton dynamics, enabling precision cancer theranostics.