Enzyme-responsive nanospheres target senescent cells for diabetic wound healing by employing chemodynamic therapy

Abstract

Evidence indicates that prolonged low-level inflammation and elevated-glucose-induced oxidative stress in diabetic wounds can accelerate senescence. The accumulation of senescent cells, in turn, inhibits cellular proliferation and migration, aggravating the inflammatory response and oxidative stress, ultimately impeding wound healing. In this study, we exploited the heightened lysosomal β-galactosidase activity detected in senescent cells to develop an innovative drug delivery system by encapsulating Fe₃O₄ with galactose-modified poly (lactic-co-glycolic acid) (PLGA) (F@GP). We found that F@GP can selectively release Fe₃O₄ into senescent cells, inducing ferroptosis via the Fenton reaction in the presence of elevated intracellular H₂O₂ levels. This showed that F@GP administration can serve as a chemodynamic therapy to eliminate senescent cells and promote cell proliferation. Furthermore, the F@GP drug delivery system gradually released iron ions into the diabetic wound tissues, enhancing the attenuation of cellular senescence, stimulating cell proliferation, promoting re-epithelialization, and accelerating the healing of diabetic wounds in mice. Our groundbreaking approach unveiled the specific targeting of senescence by F@GP, demonstrating its profound effect on promoting the healing of diabetic wounds. This discovery underscores the therapeutic potential of F@GP in effectively addressing challenging cases of wound repair. STATEMENT OF SIGNIFICANCE: The development of galactose-modified PLGA nanoparticles loaded with Fe₃O₄ (F@GP) represents a significant therapeutic approach for the treatment of diabetic wounds. These nanoparticles exhibit remarkable potential in selectively targeting senescent cells, which accumulate in diabetic wound tissue, through an enzyme-responsive mechanism. By employing chemodynamic therapy, F@GP nanoparticles effectively eliminate senescent cells by releasing iron ions that mediate the Fenton reaction. This targeted approach holds great promise for promoting diabetic wound healing by selectively eliminating senescent cells, which play a crucial role in impairing the wound healing process. The innovative utilization of F@GP nanoparticles as a therapeutic intervention offers a novel and potentially transformative strategy for addressing the challenges associated with diabetic wound healing.

Keywords: Chemodynamic therapy; Diabetic wounds; Nanomedicine; Senescence; Senescence-associated β-galactosidase.