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The current therapies for RCC are limited by drug resistance and toxic side effects. This study introduces an innovative approach that combines ginger\u2010derived exosome\u2010like nanoparticles (GELNs) with sunitinib (Su) and folic acid\u2010polyethylene glycol (FA\u2010PEG, FPD) in an active\u2010passive targeting strategy to explore its multi\u2010mechanism and synergistic therapeutic effects on RCC. GELNs are extracted via differential centrifugation combined with sucrose gradient ultracentrifugation. Metabolomics and network pharmacology predicted that GELNs may exert their anticancer efficacy via the PI3K\u2010Akt signaling pathway, which is subsequently validated through in vitro experiments. By loading Su and modifying it with FPD, FPD\u2010GELNs\/Su is constructed. The FPD modification significantly enhanced tumor targeting and amplified the Su sensitivity by reducing ABCB1\/P\u2010gp expression induced by GELNs. In vivo experiments revealed that FPD\u2010GELNs\/Su promoted M1 macrophage polarization and increased immune T\u2010cell infiltration by remodeling the tumor microenvironment, leading to significant inhibition of tumor growth and lung metastasis without causing notable liver or kidney toxicity. This study integrates network pharmacology with targeted delivery strategies, elucidating the mechanisms by which FPD\u2010GELNs\/Su inhibits RCC progression through multiple pathways, providing new insights for the development of precise and low\u2010toxicity nano\u2010therapies.<\/jats:p>","DOI":"10.1002\/advs.202512563","type":"journal-article","created":{"date-parts":[[2025,11,17]],"date-time":"2025-11-17T08:53:56Z","timestamp":1763369636000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Folic Acid\u2010Modified Ginger\u2010Derived Exosome\u2010Like Nanoparticles Co\u2010Delivering Sunitinib Suppress Renal Cell Carcinoma via PI3K\u2010Akt Pathway Inhibition, P\u2010gp Downregulation, and Macrophage 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