Harnessing Silicene‐to‐Silicic Acid Conversion for Organelle‐Specific Silica Deposition in Tumor Therapy

Abstract

ABSTRACT Inducing localized mineralized lesions offers a promising drug‐free strategy for tumor suppression, yet calcium‐phosphate systems are limited by slow crystallization, high ion requirements, and poor organelle specificity. Here, we develop a silicene‐derived nanoplatform that serves as an “inorganic silicic acid reservoir”, enabling controlled, organelle‐specific biosilicification for cancer therapy. Silicene nanosheets are sequentially engineered with tannic acid and PEI‐anchored triphenylphosphonium (TPTS), conferring high colloidal stability, efficient endosomal escape, and selective mitochondrial targeting. Within the oxidative mitochondrial milieu, TPTS undergoes programmed hydrolysis to release Si(OH) 4 , which condenses in situ to form silica directly on mitochondrial membranes. The resulting confined mineral deposits disrupt membrane potential, impede metabolite trafficking, and precipitate a catastrophic energetic collapse that drives apoptosis. This platform delivers two major advances: (1) Intracellular mineralization redefinition—precursors shift from intrinsic labile physiological ions to exogenous bio‐orthogonal nano‐reservoir, enabling sustained, site‐specific silicic acid release; (2) High therapeutic potency – organelle‐level precise therapy surpasses conventional high‐dose‐dependent cellular‐scale mineralization, achieving 81.79% tumor inhibition in ectopic models and 65.81% even in the more challenging orthotopic TNBC models, without inducing systemic toxicity. Together, these results establish a generalizable paradigm for spatially programmed mineralization therapy and position silicene as a versatile foundation for next‐generation organelle‐targeted cancer interventions.