Development and Characterization of Ginsenoside-Aconitum Lipidic Cubic Nanoparticle-Loaded Dissolving Microneedles...

A dual-drug transdermal delivery system was developed by co-encapsulating Panax notoginseng total saponins (PNS) and Aconitum alkaloids into lipidic cubic nanoparticles (LCNPs) and incorporating them into dissolving microneedles (DMNs). High-performance liquid chromatography (HPLC) methods were established and validated for simultaneous quantification of representative notoginsenosides and Aconitum alkaloids, showing high specificity, excellent linearity ( $R^2>0.999$ ), good precision (RSD < 3%), and satisfactory accuracy (recoveries 95-105%). LCNPs prepared via a precursor injection method exhibited a mean particle size of $56.9\pm 3.2$ nm with a narrow size distribution (PDI = 0.272) and high encapsulation efficiencies (> 90%). Transmission electron microscopy confirmed the fingerprint-like cubic nanostructure. The LCNP-loaded DMNs possessed sufficient mechanical strength to penetrate skin and rapidly dissolved within 20 min. In vitro permeation studies showed cumulative permeation of 96.9% for PNS and 93.9% for Aconitum alkaloids within 6 h, markedly higher than LCNPs alone (< 20% at 24 h). In vivo, the LCNP-DMN system significantly reduced acetic acid-induced writhing in mice ( $P<0.05$ ) and alleviated formaldehyde-induced arthritis in rats, with decreased joint swelling and reduced pro-inflammatory cytokines (IL-1 $\beta$ , TNF- $\alpha$ , IL-6; $P<0.01$ ), comparable to a commercial external patch. No visible dermal irritation or systemic toxicity was observed. Overall, the PNS-Aconitum LCNP-DMN system enabled synchronized dual-drug delivery with strong anti-inflammatory and analgesic efficacy and good biocompatibility, representing a promising nanostructured transdermal platform for the management of inflammatory pain conditions such as arthritis.