<i>Periplaneta americana</i> Extract-Loaded Spider Silk Protein Particles Embedded in a Thermosensitive Hydrogel for Sustained Vaginal Delivery

Vaginal drug delivery systems offer distinct advantages for treating gynecological diseases, including drug targeting and avoidance of hepatic first-pass metabolism. However, conventional formulations are rapidly cleared by vaginal mucosal fluid, which often leads to burst release, short residence time, and insufficient local drug concentrations, thereby compromising therapeutic outcomes. Herein, we developed a composite system termed PA-particles-TH, which incorporates Periplaneta americana (PA) extract-loaded spider silk protein particles (PA-particles) into a thermosensitive hydrogel (TH). PA-particles were prepared by dissolving spider silk protein in hexafluoroisopropanol, allowing self-assembly, and then physically blending the resulting particles with TH to form PA-particles-TH. The optimized PA-particles exhibited a drug-loading capacity of 9.02 ± 0.33% and encapsulation efficiency of 57.88 ± 0.21%. Their size ranged from 100 to 150 μm, and they showed excellent flowability and thermal sensitivity. Particles degraded slowly over 7 days in artificial vaginal fluid, reaching a mass loss of 37.02 ± 2.66% observed on day 78. The formulation was not significantly cytotoxic to L-929 cells, demonstrated favorable hemocompatibility, and did not induce vaginal mucosal irritation in murine models. Importantly, the PA-particles-TH formulation achieved 24 h sustained drug release via Fick diffusion and significantly prolonged vaginal retention time compared to unencapsulated particles. Collectively, these findings highlight the potential of spider silk protein-based carriers for vaginal drug delivery and offer a promising strategy for the treating gynecological diseases.