Hierarchical nanoclusters with programmed disassembly for mitochondria-targeted tumor therapy with MR imaging

Mitochondria are crucial metabolic organelles involved in tumorigenesis and tumor progression, and the induction of abnormal mitochondria metabolism is recognized as a strategy with strong potential for the exploration of advanced tumor therapeutics. Herein, hierarchical manganese silicate nanoclusters modified with triphenylphosphonium (MSNAs-TPP) were designed and synthesized for mitochondria-targeted tumor theranostics. The as-prepared MSNAs-TPP retains considerable dimensional and structural stability in the neutral physiological environment, favoring its accumulation at the tumor site. More interestingly, MSNAs-TPP may disassemble in a responsive manner to an acidic tumor microenvironment into ultrasmall manganese silicate nanocapsules (∼6 nm), enabling deep tumor penetration and mitochondria targeting. When reaching the mitochondria, the nanocapsules effectively deplete mitochondrial glutathione (GSH), and simultaneously release catalytic Mn²⁺ ions to induce amplified oxidative stress in the structure with the enriched CO₂ and H₂O₂ from mitochondria metabolism. As a result, MSNAs-TPP presents considerable antitumor effect without a clear side effect, both in vitro and in vivo. The study may provide an alternative concept in the development of intelligent nanotherapeutics for tumor treatment with high efficacy.