pH-Responsive Hydrogel-Mediated Transdermal Co-delivery of Triamcinolone Acetonide and 5-Fluorouracil for Hypertrophic Scar Treatment via Regulating Macrophage Polarization and Exerting Antifibrotic Effects

Hypertrophic scar (HS) is a fibrotic disorder caused by imbalanced tissue repair after skin injury. Its core features include persistent inflammation and excessive collagen deposition. Current clinical treatments are limited by poor efficacy, severe local adverse reactions, and low transdermal delivery efficiency of topical drugs. In this study, a pH-responsive borax-dextran hydrogel (TA/5-FU@BDHs) co-loaded with triamcinolone acetonide (TA) and 5-fluorouracil (5-FU) was developed for transdermal treatment of HS. First, (2-hydroxypropyl)-β-cyclodextrin (HP-β-CD) was used to prepare HP-β-CD@TA/5-FU inclusion complexes, taking advantage of its hydrophobic cavity to encapsulate TA and 5-FU, thereby enhancing the aqueous solubility and stability of the two drugs. The inclusion complexes were encapsulated into a borax-cross-linked dextran hydrogel, forming a composite carrier for pH-responsive drug release and efficient transdermal delivery. The physicochemical properties of the inclusion complexes and hydrogel were systematically characterized by particle size and zeta potential analysis, storage stability testing, X-ray diffraction (XRD), differential scanning calorimetry (DSC), scanning electron microscopy (SEM), and swelling and degradation behavior assessment. It enabled rapid drug release in the weakly acidic HS microenvironment, significantly promoting transdermal absorption and cellular uptake. In vitro and in vivo studies demonstrated that TA/5-FU@BDHs induced macrophage polarization from M1 to M2 phenotype by modulating inflammatory mediators, exerting anti-inflammatory effects. Meanwhile, it inhibited abnormal activation of hypertrophic scar fibroblasts (HSFs) and downregulated the expression of fibrosis-related proteins. In summary, TA/5-FU@BDHs enable precise pH-responsive release, effectively ameliorate the core pathological processes of HS via macrophage polarization, and exert anti-inflammatory and antifibrotic effects. This system provides a safe, effective, and clinically translatable strategy for transdermal local treatment of HS.