Wang Yuanyuan, Zhong Caiyun, Wang Kexin, Shen Shihong, Fan Daidi
Engineering Research Center of Western Resource Innovation Medicine Green Manufacturing, Ministry of Education, School of Chemical Engineering, Northwest University, Xi'an 710127, China.
Biotechnology & Biomedical Research Institute, Northwest University, Xi'an 710127, China.
Gels. 2025 May 23;11(6):384. doi: 10.3390/gels11060384.
Microcirculation damage, dermal thickening, and difficulty in the spatiotemporal coordination of key platelet factor 4 (CXCL4) and transforming growth factor-β (TGF-β) contribute to the lack of effective treatments for systemic sclerosis (scleroderma, SSc). To address these challenges, we proposed a novel synergistic drug combination of ginsenoside Rk3 (CXCL4 regulator) and metformin (Met, TGF-β regulator) based on molecular docking and developed an ultra-long release, dual-target regulation hydrogel microneedle system (Rk3/Met URS MN). The rapidly dissolving tips of this hydrogel microneedle consisted of polyvinyl alcohol and polyvinylpyrrolidone, and were loaded with polydopamine-coated, coordination-induced self-assembled Rk3/Met nanomedicines. These micro-tips could spatiotemporally synchronize transdermal delivery of the hydrophobic Rk3 and hydrophilic Met, providing ultra-long release for up to 10 days with a single administration. The recombinant collagen CF-1552/oxidized pullulan-based (CAOP) hydrogel backing exhibited skin self-adhesiveness and excellent mechanical properties and could perform localized moisture retention and free radical scavenging at the lesion site. In vitro and in vivo efficacy studies, along with bioinformatics analysis of RNA sequencing, demonstrated that the Rk3/Met URS MN achieved immune modulation, anti-inflammatory effects, angiogenesis promotion, and antifibrosis in SSc through synergistic CXCL4/TGF-β dual-target regulation. Notably, on the 10th day, the dermal thickness decreased from 248.97 ± 21.3 μm to 152.7 ± 18.1 μm, with no significant difference from the normal group, indicating its significant potential in clinical applications in SSc.
微循环损伤、皮肤增厚以及关键血小板因子4（CXCL4）和转化生长因子-β（TGF-β）在时空协调方面的困难，导致系统性硬化症（硬皮病，SSc）缺乏有效的治疗方法。为应对这些挑战，我们基于分子对接提出了一种人参皂苷Rk3（CXCL4调节剂）和二甲双胍（Met，TGF-β调节剂）的新型协同药物组合，并开发了一种超长释放、双靶点调控水凝胶微针系统（Rk3/Met URS MN）。这种水凝胶微针的快速溶解尖端由聚乙烯醇和聚乙烯吡咯烷酮组成，并负载有聚多巴胺包覆、配位诱导自组装的Rk3/Met纳米药物。这些微尖端可以在时空上同步疏水性Rk3和亲水性Met的透皮递送，单次给药可提供长达10天的超长释放。基于重组胶原蛋白CF-1552/氧化普鲁兰的（CAOP）水凝胶背衬表现出皮肤自粘性和优异的机械性能，并且可以在病变部位进行局部保湿和自由基清除。体外和体内疗效研究以及RNA测序的生物信息学分析表明，Rk3/Met URS MN通过协同CXCL4/TGF-β双靶点调控在SSc中实现了免疫调节、抗炎作用、促进血管生成和抗纤维化。值得注意的是，在第10天，皮肤厚度从248.97±21.3μm降至152.7±18.1μm，与正常组无显著差异，表明其在SSc临床应用中具有巨大潜力。
