Innovative epidermal-penetrating nanogels with microenvironment-adaptive pH responsiveness orchestrate glucose homeostasis reprogramming and spatiotemporally coordinated therapeutic cascades for precision diabetic wound therapy

Diabetic wounds are typified by a highly complex pathological microenvironment, marked by hyperglycemia, cellular dysfunction, impaired angiogenesis, and defective tissue regeneration. These factors collectively hinder the normal healing process. In response to such multifaceted challenges, responsive nanotherapeutic platforms with sequential release capabilities have emerged as a promising solution. Herein, we developed a highly adaptable and multifunctional nanocare platform designed to provide spatiotemporal and compositional co-regulation for diabetic wound healing. A core-shell structured nanodressing was meticulously constructed, namely a pH-responsive polydopamine (PDA) shell, an insulin-loaded interlayer and a bioactive core formed by esterification-driven self-assembly of synthetic polymers, polyphenols, and amino acids. Comprehensive <i>in vitro</i> and <i>in vivo</i> studies demonstrated excellent biocompatibility, along with significant anti-inflammatory, pro-angiogenic, and regenerative efficacy. Efficient transdermal penetration and activation of key regenerative signaling pathways including Notch, VEGF, and PI3K/AKT were observed, which enhanced endothelial cell proliferation, migration, and tubulogenesis. These findings underscore the therapeutic potential of this intelligent nanoplatform in orchestrating the diabetic wound microenvironment and suggest broad applicability in complex disease interventions requiring coordinated multi-target modulation.