Mini Hyaluronic Acid-modified Nanoliposomes for Topical Co-Delivery of Paeonol, Totarol and Ergothioneine: A Synergistic Adjuvant Therapy for Acne

Adjuvant skincare formulations possessing anti-inflammatory and antibacterial properties can alleviate treatment-related side effects and enhance patient adherence in acne management. Paeonol (PAE), totarol (TOT), and ergothioneine (ERG) demonstrate promising anti-acne activity. However, their clinical translation is hindered by poor solubility, limited stability, and insufficient skin permeation. To address these limitations, we co-encapsulated PAE, TOT, and ERG into hyaluronic acid (HA)-modified nanoliposomes (NLPs). Compared to the NLPs modified with HA with high molecular weights, those formulated with miniHA (3-10 kD a ) exhibited superior skin penetration capability and cellular uptake efficiency. The miniHA modified NLPs co-encapsulated PAE, TOT, and ERG (PTE-NLPs) exhibited excellent biocompatibility in both in vitro cytotoxicity assay and chicken embryo chorionic allantoic membrane irritation assays. Compared to free functional ingredients, PTE-NLPs demonstrated significantly enhanced anti-inflammatory and antibacterial efficacy in cellular assays. Furthermore, in 3D skin models, PTE-NLPs suppressed Transient Receptor Potential Vanilloid 1 (TRPV1) expression, indicating a potential mechanism for attenuating neuronal hyperreactivity. The anti-inflammatory activity was subsequently validated in vivo. These findings collectively demonstrate that miniHA-modified NLPs provide a safe and efficient platform for co-delivering synergistic anti-acne actives, highlighting their strong potential as an adjuvant therapy for acne management.