Abstract

Background: Acne vulgaris is a prevalent inflammatory skin disorder characterized by a pathological triad of follicular hyperkeratosis, Cutibacterium acnes proliferation, and aberrant inflammation, often leading to tissue damage and scarring. The current treatment methods mainly rely on antibiotics, which have drawbacks such as bacterial resistance and insufficient promotion of tissue regeneration. There is an urgent need for a strategy that simultaneously targets bacterial elimination and active tissue repair.

Methods: We developed an alginate-based hydrogel co-loaded with Phellodendron bark Extract (PBE) and Human Umbilical Cord Mesenchymal Stem Cell-derived Exosomes (HucMSC-Exo), call ed PE gel. The antibacterial activity of PBE against C. acnes, Staphylococcus aureus, and Escherichia coli was evaluated through broth microdilution, plate counting, biofilm formation, and live/dead staining assays. The hydrogel's physicochemical properties, drug release profile, and in vitro antibacterial durability were characterized. A rat ear acne model induced by C. acnes was established to assess the in vivo therapeutic efficacy of PE gel by measuring swelling resolution, bacterial load, histopathological changes (H&E and Masson's trichrome staining), and expression of inflammatory and regenerative markers (TNF-α, IL-6, CD31, VEGF via immunohistochemistry).

Results: PBE demonstrated potent, broad-spectrum antibacterial and anti-biofilm activity, with a minimum inhibitory concentration of ~5 mg/mL against C. acnes. Its efficacy was unaffected by the presence of HucMSC-Exo. The PE gel facilitated sustained release of PBE and exhibited enhanced and prolonged antibacterial effects in vitro , which can maintain good antibacterial effect within 72 hours rather than the original 5 hours . In the animal model, PE gel treatment resulted in superior acne resolution compared to gels containing PBE or Exo alone. It significantly reduced ear swelling, decreased tissue bacterial load by over 99.8%, mitigated inflammatory infiltration, diminished follicular hyperkeratosis, and promoted organized collagen remodeling. P athology studies shows that the PE gel has a synergistic effect: PBE primarily mediated antibacterial and anti-inflammatory actions (suppressing TNF-α/IL-6), while HucMSC-Exo primarily drove pro-regenerative processes (enhancing VEGF/CD31-mediated angiogenesis and collagen remodeling).

Conclusion: The PE gel, through a synergistic "antibacterial-resist inflammation-repair" axis, effectively disrupts the vicious cycle of acne pathogenesis. This strategy combines sustained antimicrobial activity with potent anti-inflammatory and regenerative signals, offering a promising and comprehensive non-antibiotic therapeutic platform for a more comprehensive management of acne vulgaris.