Tumor microenvironment-activated nanoplatform via Fe³⁺-mediated self-assembly for synergistic chemodynamic/gene/chemo...

Nucleic acid-based nanotherapeutics hold great promise for tumor treatment, yet face challenges in drug loading capacity, stability during delivery, and controlled intracellular release. Herein, we propose a carrier-free, tumor microenvironment (TME)-responsive nanoplatform (FAM NPs-FA) constructed via coordination-driven self-assembly of Survivin antisense oligodeoxynucleotide (ASO), methotrexate (MTX), and Fe³⁺ ions. The resulting nanocomposites demonstrate high drug loading, enhanced serum stability, and intrinsic synergistic activity by integrating chemodynamic, gene, and chemotherapeutic therapies. Upon cellular uptake by tumor cells, the acidic TME triggers disassembly of the nanoplatform, releasing Fe³⁺, Survivin ASO, and MTX. Intracellular glutathione reduces Fe³⁺ to Fe²⁺, which catalyzes hydrogen peroxide to generate highly cytotoxic hydroxyl radicals for chemodynamic therapy (CDT). Meanwhile, the released Survivin ASO specifically silences Survivin mRNA, suppressing anti-apoptotic protein expression, and accelerating tumor cell apoptosis. Moreover, combined with the chemotherapeutic effects of MTX, this nanoplatform demonstrates exceptional synergistic therapeutic efficacy against tumors while minimizing adverse impacts on healthy tissues, thus opening a versatile and effective carrier-free platform for TME-responsive synergistic cancer therapy integrating gene regulation, reactive oxygen species generation, and chemotherapy.