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

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.