Nanofibrous Poly(amino acid ester) Dressing for Promoting Diabetic Wound Healing via Spatiotemporal Coordination of Immunomodulation and Tissue Regeneration

Abstract Effective healing of diabetic wounds requires spatiotemporal coordination of immunoregulation and tissue regeneration, which is often overlooked in conventional treatments. Here, we developed an extracellular matrix-mimicking dressing, termed ANM, that modulates arginine utilization within the diabetic wound microenvironment to re-establish the spatiotemporal coordination of healing. ANM was in situ fabricated by hand-held electrospinning using a rationally designed arginine- and norvaline-based poly(ester amide), yielding a conformable and breathable nanofibrous dressing. Its porous and hydrolyzable structure enabled moisture- and enzyme-responsive degradation, allowing sustained release of arginine- and norvaline-containing degradants. These bioactive degradants cooperatively modulated macrophage phenotypic transitions, initially promoting a timely proinflammatory response, followed by a spontaneous shift toward a pro-reparative state, thereby restoring the temporally sequenced inflammatory program in diabetic wounds. Meanwhile, ANM locally upregulated inducible nitric oxide synthase (iNOS) and arginase-1 in the peri-wound epidermis, spatially promoting the proliferation and differentiation of epidermal keratinocytes and accelerating re-epithelialization. In contrast to commercial dressings that failed to support healing and even led to progressive deterioration over 21 days, ANM significantly promoted collagen deposition and angiogenesis and accelerated wound closure in db/db mice by 14 days. This work offers a promising strategy for treating chronic nonhealing wounds through spatiotemporal metabolic modulation.