Core-Shell Microneedle Patches Co-Loaded with Gymnema Sylvestre Extract and IL-4 Accelerate Diabetic Wound Repair via Inflammatory Microenvironment Remodeling

Abstract

Chronic wound healing remains a persistent challenge clinically, particularly in diabetic wounds, where hyperglycemia drives sustained activation of the AGE–RAGE-associated signaling within the wound bed, precipitating excessive ROS generation and persistent inflammation that together stall tissue repair and erode quality of life. To address this, we developed a core–shell microneedle (GS + IL-4@MN) patch loading Gymnema sylvestre (GS) extract and interleukin-4 (IL-4) as a promising therapeutic strategy. The patch comprised a 10 × 10 array of conical needles and the optimized shell-loading concentration of GS was determined to be 1.0 mg/mL. The GS-loaded outer shell can suppress the release of pro-inflammatory mediators, scavenge ROS, and strengthen antioxidant defenses, thereby attenuating local inflammation; the IL-4-encapsulated core induces macrophage polarization toward the M2 phenotype, mitigates the pro-inflammatory microenvironment, and modulates T-cell immunity, while enhancing cellular proliferation and migration to support tissue regeneration. In diabetic wound models, GS + IL-4@MN achieved wound-closure rates of 64.72 ± 6.3% at day 3 and 85.80 ± 3.6% at day 7, and re-epithelialization reached 91.52 ± 2.1% by day 14. Moreover, collagen deposition increased to 79.38 ± 4.3%, CD31-positive neovascularization reached 70.50 ± 3.7%, and the M1/M2 ratio decreased to 0.3, indicating marked inflammatory resolution and regenerative activation. In summary, this core–shell MN system achieves multidimensional regulation of the pathological microenvironment of diabetic wounds through a dual mechanism: outer-layer inflammatory suppression and inner-layer microenvironment reset, and offers a new avenue for promoting diabetic wound healing.