Precise Starving Therapy via Physiologically Dependent Photothermal Conversion Promoted Mitochondrial Calcification Based on Multi‐Functional Gold Nanoparticles for Effective Tumor Treatment

Abstract Starving therapy based on tumor calcification has been considered as a promising strategy with high biosafety for tumor treatment. However, the limited calcium (Ca²⁺) concentration in/around tumor tissue as well as the slow and uncontrollable process of the physiological calcification are all challenges for its application. Herein, a sialic acid (SA, Ca²⁺ chelator), folic acid (FA, tumor targeting agent) and triphenylphosphine (TPP, mitochondrial targeting agent) co‐modified gold nanoparticles (SFT‐Au) are fabricated to take advantage of the abundant Ca²⁺ in mitochondria as well as the Ca²⁺ collection and Ca²⁺ dependent photothermal property of SFT‐Au to achieve a precise and promoted calcification of tumor mitochondria for effective starving therapy. During therapy, the SFT‐Au will first accumulate in tumor mitochondria through stepwise targeting processes medicated by FA and TPP. After that, the SA further binds with the over‐expressed Ca²⁺ in tumor mitochondria to induce the aggregation of SFT‐Au, which not only gathers Ca²⁺ to initiate the calcification of mitochondria, but in situ generates photothermal agent to perform photothermal conversion under 808 nm irradiation to promote the calcification, resulting in effective prohibition of the energy metabolism in tumor cells for starving therapy and continuously photothermal damage of tumor cells to enhance the therapeutic efficiency.