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Codonopsis pilosula, a traditional food\u2013medicine homologous plant, is recognized for its anti-aging properties. However, its lipophilic components (designated as CP-L) remain insufficiently explored. Methods: Herein, we developed a thermosensitive nanogel encapsulating CP-L-loaded transferosomes (CP-L nanogel) to enhance topical delivery and evaluated its effects in both a UV-induced photoaging mouse model and UVB-irradiated HaCaT keratinocytes. Results: In UV-induced mice, topical application of the nanogel markedly reduced skin wrinkling and epidermal hyperplasia, with epidermal thickness decreased by 83.2% compared to the model group (p &lt; 0.01), and restored skin elasticity and collagen deposition, as evidenced by a 35.5% increase in collagen area fraction (p &lt; 0.01). Correspondingly, in UVB-irradiated HaCaT cells, it significantly increased cell viability from 53.0 \u00b1 9.6% to 89.4 \u00b1 1.0% (p &lt; 0.01) and suppressed apoptosis from 30.1 \u00b1 0.48% to 12.4 \u00b1 0.66% (p &lt; 0.01). Furthermore, the CP-L nanogel consistently attenuated oxidative stress, with SOD, CAT, and GSH-Px activities increased by 73.1%, 188.1%, and 18.2%, respectively (p &lt; 0.01), and MDA levels reduced by 71.0% (p &lt; 0.01), while inflammatory responses were suppressed, as TNF-\u03b1, IL-1\u03b1, IL-1\u03b2, and IL-6 levels decreased by 28.3%, 22.6%, 12.8% and 31.9%, respectively (p &lt; 0.01). Mechanistically, transcriptomic and molecular analyses revealed that the nanogel potently inhibited the UV-induced activation of the FGFR\/PI3K\/AKT\/mTOR\/p70S6K signaling cascade at both transcriptional and protein levels, with the phosphorylation levels of FGFR, PI3K, AKT, mTOR, and p70S6K significantly reduced by 43.9%, 30.9%, 38.8%, 34.9%, and 57.3%, respectively (p &lt; 0.01). Molecular docking and dynamics simulations identified isofuranodienone and aromadendrene oxide-(2) as key constituents with high-affinity, stable binding to FGFR1 and AKT1. The cytoprotective effect of the nanogel was completely abolished by co-treatment with the FGFR inhibitor PD173074, confirming functional reliance on this pathway. Enhanced cellular delivery of the formulation was directly demonstrated by flow cytometry, showing an approximately 1.8-fold increase in cellular uptake compared to the free drug (p &lt; 0.01). Conclusions: Collectively, these results demonstrated that the CP-L nanogel alleviated skin photoaging through a multi-faceted mechanism involving enhanced cellular delivery, potent antioxidant and anti-inflammatory activities, and specific inhibition of the FGFR\/PI3K\/AKT\/mTOR signaling cascade, highlighting its potential as a multitargeted topical agent derived from an edible plant.<\/jats:p>","DOI":"10.3390\/pharmaceutics18070869","type":"journal-article","created":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T05:32:17Z","timestamp":1784266337000},"page":"869","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Codonopsis pilosula Lipophilic Extract-Loaded Thermosensitive Nanogel Attenuates Skin Photoaging by Inhibiting the FGFR\/PI3K\/AKT\/mTOR Pathway"],"prefix":"10.3390","volume":"18","author":[{"given":"Jiangtao","family":"Zhou","sequence":"first","affiliation":[{"name":"School of Pharmacy, Shanxi Medical University, Taiyuan 030001, China"},{"name":"Medicinal Basic Research Innovation Center of Chronic Kidney Disease, Ministry of Education, Shanxi Medical University, Taiyuan 030001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhui","family":"Ge","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Shanxi Medical University, Taiyuan 030001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ran","family":"Li","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Shanxi Medical University, Taiyuan 030001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuoyang","family":"Cheng","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Shanxi Medical University, Taiyuan 030001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianping","family":"Gao","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Shanxi Medical University, Taiyuan 030001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Zheng","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Shanxi Medical University, Taiyuan 030001, China"},{"name":"Medicinal Basic Research Innovation Center of Chronic Kidney Disease, Ministry of Education, Shanxi Medical University, Taiyuan 030001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Geng, R., Kang, S.-G., Huang, K., and Tong, T. 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