Novel dissolving microneedles incorporating natural carrier-free self-assembled nanoparticles synergized with electroacupuncture for diabetic wound healing.

Diabetic wounds (DW) are one of the most common complications of diabetes with complex pathogenesis, causing high morbidity and disability. Conventional therapies fail to resolve multiple obstacles to DW healing, urgently requiring efficient and safe novel interventions. Compounds from medicine and food homology substances have attracted widespread attention owing to their superior biosafety and diverse pharmacological activities. Herein, carrier-free APC and GQS nanoparticles were manufactured separately via self-assembly using medicine and food homology bioactive components, including astragalus polysaccharide, chlorogenic acid, quercetin, β-sitosterol, and glycyrrhizin acid. Subsequently, dissolvable APC@GQS@MNs co-loaded with APC and GQS were constructed using polyvinylpyrrolidone, hyaluronic acid, and aloe vera as matrix materials. Physicochemical characterization confirmed that APC@GQS@MNs have a well-defined conical morphology, satisfactory mechanical strength, and favorable skin penetration. The APC@GQS@MNs also enabled efficient selective scavenging of cytotoxic reactive oxygen species (ROS), while physiological ROS were less affected. Meanwhile, APC@GQS@MNs exhibited favorable biocompatibility, reduced intracellular ROS levels, ameliorated oxidative stress-induced damage to cell proliferation, migration and tube formation, promoted M1 to M2 macrophage polarization, and effectively inhibited the growth and biofilm formation of Staphylococcus aureus and Escherichia coli. In vivo results showed that APC@GQS@MNs promoted collagen deposition, re-epithelialization, and reduced local inflammatory infiltration in DW by upregulating CD31, CD163, IL-10 and suppressing iNOS, NF-κB, and TNF-α signaling. Notably, APC@GQS@MNs combined with electroacupuncture exerted synergistic effects, which further ameliorated the wound microenvironment and markedly accelerated wound healing and tissue regeneration. Such synergistic therapy modulates local wound states and inflammatory responses, laying a promising foundation for the management of DW.