目的 制备盐酸小檗碱自组装纳米粒（berberine hydrochloride self-assembled nanoparticles，BBH-SAN），在无需载体材料的前提下，实现稳定自组装，并系统评价其理化性质及体外透皮性能。方法 采用pH驱动法制备BBH-SAN，以平均粒径、多分散指数（polydispersity index，PDI）作为评价指标优化工艺。运用扫描电子显微镜（scanning electron microscopy，SEM）、傅里叶变换红外光谱（Fourier transform infrared spectroscopy，FT-IR）、热重分析（thermogravimetric analysis，TG）及X射线衍射（X-ray diffraction，XRD）分析进行表征；结合分子动力学模拟揭示自组装行为；通过体外透皮实验考察药物透皮性能。结果 制备的BBH-SAN在SEM下呈片状结构，平均粒径为（385.67±13.50）nm，PDI为0.06±0.04，ζ电位为（-34.03±1.01）mV，包封率为（87.57±0.05）%。XRD结果显示，BBH-SAN衍射峰重构与结晶度下降，FT-IR特征峰展宽与减弱，提示BBH由规则晶态向低晶态聚集转变。分子动力学模拟揭示，BBH-SAN的形成是由范德华相互作用主导，静电相互作用调控，氢键网络协同稳定的自组装过程。体外透皮实验中，BBH-SAN在24 h内的累积透过量（Q_n）为（61.25±1.78）μg/cm²，皮肤滞留量（Q_s）、真皮滞留量（Q_d）和角质层滞留量（Q_sc）均显著高于BBH原料药（P＜0.001）。结论 通过加热辅助pH值驱动法，无需载体即可实现BBH的稳定自组装，所得纳米粒粒径均一、分散性好、热稳定优异，并显著改善透皮性能，为生物碱类药物的自组装递送提供了新策略。

Objective To prepare berberine hydrochloride self-assembled nanoparticles (BBH-SAN) and realize stable self-assembly of BBH without carrier materials, and to systematically evaluate its physicochemical properties and in vitro transdermal performance. Methods BBH-SAN were prepared using a heat-assisted pH-driven method, with average particle size and polydispersity index (PDI) as evaluation indicators for process optimization. The nanoparticles were characterized by scanning electron microscopy (SEM), Fourier-transform infrared spectroscopy (FT-IR), thermogravimetric analysis (TG), and X-ray diffraction (XRD). Molecular dynamics simulations were employed to elucidate the self-assembly mechanism of BBH-SAN, and in vitro transdermal experiments were conducted to investigate the drug’s transdermal performance. Results The prepared BBH-SAN exhibited lamellar sheet structures under SEM, with an average particle size of (385.67 ± 13.50) nm, a PDI of 0.06 ± 0.04, the ζ potential was determined to be (−34.03 ± 1.01) mV, and an encapsulation efficiency of (87.57 ± 0.05)%. XRD results indicated peak reconstruction and reduced crystallinity, while FT-IR revealed broadening and attenuation of characteristic peaks, suggesting a transition of BBH from a regular crystalline state to a low-crystalline aggregated form. Molecular dynamics simulations revealed that the formation of BBH-SAN is a self-assembly process dominated by van der Waals interactions, regulated by electrostatic interactions, and stabilized synergistically by hydrogen-bond networks. In the in vitro transdermal experiments, the cumulative permeation amount of BBH-SAN within 24 h was (61.25 ± 1.78) μg/cm², and the skin retention (Q_s), dermal retention (Q_d), and stratum corneum retention (Q_sc) of BBH-SAN were all significantly higher than those of BBH (P < 0.001). Conclusion This study achieved the stable self-assembly of berberine hydrochloride without the use of any carrier through a heat-assisted pH-driven method. The resulting nanoparticles exhibit uniform particle size, good dispersibility, excellent thermal stability, and significantly improved transdermal performance, providing a new strategy for the self-assembly delivery of alkaloid drugs.

军队医疗与医药服务能力建设与提升专项计划（2023ZY031）；空军特色医学中心人才培养计划（2025RCQN02）；空军特色医学中心人才培养计划（2025RCQN11）