Intracellular Bottom‐up Synthesis of Ultrasmall CuS Nanodots in Cancer Cells for Simultaneous Photothermal Therapy and COX‐2 Inactivation

Abstract The clinical application of photothermal therapy (PTT) is limited by the accuracy of thermal damage and the risk of tumor metastasis and relapse induced by hyperthermia‐related inflammation. Intracellular bottom‐up synthesis (iBuS) of CuS nanoparticles from small‐molecule precursors inside tumor cells triggered by tumor specific stimuli is a promising strategy to enhance the precision of PTT treatment and reduce the risk of nondegradable metal nanoparticles. Herein, monolocking nanoparticles (MLNPs) with Cu‐meloxicam complexes encapsulated by human serum albumin (HSA) are reported, which efficiently form CuS nanodots via the elevated concentration of endogenous H 2 S inside tumor cells and meanwhile release meloxicam for anti‐inflammatory effects. The intracellular bottom‐up fabrication of CuS nanodots is directly visualized by TEM. An enhanced PTT effect is observed with 4T1 cells caused by additional meloxicam‐induced inactivation of the COX‐2 enzyme. After systemic administration, MLNPs completely ablate tumors under laser exposure, simultaneously inhibiting the inflammation induced by photothermal damage, and can be cleared via the kidney into urine. This strategy provides a new route for activated multimodal therapy, which could be applicable to precisely combat cancer.