Precision therapy through breaking the intracellular redox balance with an MOF-based hydrogel intelligent nanobot for enhancing ferroptosis and activating immunotherapy

With the advancement and development of nanomedicine, tumor precision therapy provides technical support for effective accumulation and targeted drug delivery, and reduces toxic side effects. In cancer cells, breaking the redox balance could induce cancer cell death. Herein, a novel iron-containing intelligent hydrogel nanobot (FeSe₂-Ce6/MOF@HA/PEI/CpG@HHPA NPs, abbreviated as FSMH) is proposed to break the intracellular redox balance and trigger the immune response. The as-fabricated multifunctional FSMH could not only exert Fenton reactions in the acidic tumor microenvironment, converting hydrogen peroxide (H₂O₂) into highly toxic hydroxyl radicals (˙OH), but also effectively consume GSH to attenuate the intracellular oxidative stress. The negative charge of the FSMH nanohydrogel system guarantees its superexcellent stabilization in blood circulation and optimal tumor collection. Subsequently, the surface charge of the endocytosed FSMH was transformed to a positive charge after exposure to the acidic tumor environment, further improving its tumor collection and locally releasing Fe ions and immune adjuvants. Furthermore, Ce6 was released in a pH-responsive manner in the acidic microenvironment. In the presence of near-infrared light, singlet oxygen was produced by the FSMH nanohydrogel system, to ablate tumors and promote the maturation of dendritic cells, achieving the precision-combined strategies effect of CDT, PDT, and immunotherapy.