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.

berberine hydrochloride  /  self-assembled nanoparticles  /  in vitro transdermal  /  molecular dynamics simulation  /  transdermal drug delivery  /  pH-driven