Engineered skin commensal nanogels mitigate psoriasiform inflammation through dual regulation of cutaneous flora and host immunity.

Psoriasis is a chronic inflammatory skin disorder characterized by immune dysregulation and alterations in the cutaneous microbiota. Current microbiome-targeted therapeutic strategies predominantly involve the topical delivery of live probiotics using hydrogel platforms. However, these approaches are hindered by limitations such as poor bacterial viability, transient colonization, and unresolved safety concerns, while often failing to address systemic immune dysfunction. To overcome these challenges, we developed nanogels derived from Staphylococcus epidermidis lysates via EDC/NHS crosslinking. The optimized formulation exhibited a uniform hydrodynamic diameter of 98.3 ± 30.2 nm and remained stable for up to 5 days without significant protein degradation. Leveraging their sub-100 nm size, these nanogels enabled multiple therapeutic mechanisms. First, they penetrated the epidermal barrier through psoriatic scales and were internalized by target cells, leading to suppressed keratinocyte hyperproliferation and reduced local inflammation. Second, they trafficked systemically via the cutaneous microvasculature, resulting in decreased activation of splenic dendritic cells (CD11c + CD80+) and normalization of the CD4+/CD8+ T-lymphocyte ratio. Concurrently, residual nanogels retained on the skin surface selectively inhibited the proliferation of Staphylococcus aureus while promoting the enrichment of commensal Staphylococcus species, thereby restoring microbial homeostasis and reinforcing barrier integrity. This strategy addresses key limitations of conventional live biotherapeutics by leveraging the enhanced biocompatibility of bacterial components and the multifunctional advantages of nanoscale delivery. It offers a synergistic and safe approach for effective psoriasis management.