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Protons play a crucial regulatory role in the behavior, metabolism, and signaling pathways of cancer cells. Precise intracellular pH control is a highly promising therapeutic strategy for tumors, but achieving precise proton-level regulation remains a significant challenge. This study constructs a near-infrared light-controlled nano-proton delivery system based on upconversion nanoparticles (UCNPs). By surface modification with photolytic acid molecules (PA) and ferrocene (Fc), UCNPs emit ultraviolet-visible light to activate PA upon 980 nm near-infrared light excitation, enabling instantaneous H⁺ release and acidification of the tumor microenvironment. This acute acid stress can reduce glucose uptake in tumor cells by 50%, inhibit the mTOR signaling pathway, trigger excessive autophagy, and cause mitochondrial dysfunction and endogenous apoptosis. This is defined as proton-mediated autophagy-induced apoptosis (PAA).
Meanwhile, Fc is biodegradable and has fluorescence quenching properties. Upon H⁺ triggering degradation, UCNPs regain their near-infrared upconversion luminescence at 800 nm, enabling real-time visualization and quantitative measurement of proton accumulation. After intravenous administration, this nano-therapeutic agent can reduce glioma tumor weight by 6 times and effectively increase intracellular proton levels. It efficiently triggers the PAA effect under non-invasive near-infrared irradiation. This work constructs a spatiotemporally controllable platform for intracellular proton dynamic regulation in tumors, providing new ideas for precise tumor diagnosis and treatment. This research is titled "Near-Infrared Upconversion Modulation of Intracellular Protons for Autophagy-Induced Apoptosis" and was published in Advanced Materials in 2026; 0:e23657.
Paper link: https://www.x-mol.com/paper/2049976271102246912
