Proteoglycan Mimetics‐Based Antimicrobial and Anti‐Inflammatory Microneedles Restoring Dysregulated Lipid Metabolism and Suppressing Skin Atrophy for Acne Treatment

ABSTRACT Over 15% of acne patients manifest moderate to severe clinical presentations, accompanied with bacterial infection, long‐term inflammatory responses, dysregulated lipid metabolism, and post‐acne skin atrophy. Although microneedles (MNs) represent an effective transdermal drug delivery system for acne treatment, the therapeutic effects on the restoration of dysregulated lipid metabolism and the prevention of atrophic acne scars are still lacking. Herein, we develop proteoglycan‐mimetic comb polymer (HMC)‐based dissolving microneedles (HMC‐PEP MNs) with encapsulation of therapeutic peptides. This system effectively targets the acne pathophysiological pathways involving bacterial colonization, lipid dysregulation, chronic inflammation and impaired tissue repair. Specifically, HMC enables sustained release of antimicrobial and anti‐inflammatory peptides via multiple non‐covalent interactions. HMC‐PEP MNs display significant efficacy via eradicating Cutibacterium acnes infection, suppressing pro‐inflammatory mediator expression, and reducing the TREM2/M2 macrophage ratio. Integrated transcriptomic and metabolomic analysis reveals that HMC‐PEP MNs effectively regulate cholesterol and linoleic acid metabolism, inhibit pro‐inflammatory signaling transduction, and reduce keratinocyte proliferation and differentiation by inhibiting the IGF1/IGF1R/PI3K/AKT/mTOR signaling pathway. Interestingly, HMC‐PEP MNs also promote collagen synthesis and ameliorate fibroblast dysfunction, thereby preventing the formation of post‐acne dermal atrophy. This study presents an effective therapeutic strategy for acne and elucidates the underlying mechanisms of HMC‐PEP MNs, demonstrating considerable promise for clinical translation.