Smart Nanoparticles Disrupting Energy Supply through Triple Mechanisms to Kill Tumors via Dual Disruption of Mitochondria and Lysosomes

Abstract Targeting mitochondrial disruption as a strategy for inhibiting cancer cell proliferation presents a promising therapeutic approach. However, the process of mitophagy plays a protective role in cancer cells by aiding in damage repair, regulating energy metabolism, and promoting the development of drug resistance. Therefore, designing precise therapies that selectively damage mitochondria while inhibiting mitophagy remains a challenge. This study develops a biomimetic nanoplatform (MTCA@C) with hollow MnO 2 as the core, loaded with tetrandrine and mitochondrial‐targeted photosensitizer (Ce6‐Apt), and coated with a cell membrane. Under the targeting of the ligand and irradiation of external near‐infrared light, Ce6‐Apt reaches the mitochondria to induce photodynamic reactions causing mitochondrial dysfunction, while also activating mitophagy. Tetrandrine induces lysosomal alkalinization, effectively disrupting the mitophagic flow, and Tet also causes macropinocytosis, characterized by excessive intracellular vacuole accumulation and expansion, leading to cell rupture and ultimately inducing methuosis. Notably, the synergistic effect of these three mechanisms cuts off the energy supply of tumor cells, achieving spatiotemporally controlled precision therapy. In summary, a biomimetic nanoplatform is designed that precisely disrupts the interaction between mitochondria and lysosomes to impair the compensatory energy supply of tumors, addressing the challenge of drug resistance in cancer treatment.