Folic Acid‐Modified Ginger‐Derived Exosome‐Like Nanoparticles Co‐Delivering Sunitinib Suppress Renal Cell Carcinoma via PI3K‐Akt Pathway Inhibition, P‐gp Downregulation, and Macrophage Reprogramming

FPD‐GELNs co‐deliver Su and bioactive components. This active‐passive dual‐targeting strategy suppresses the progression of RCC through the following mechanisms: 1) inhibition of the PI3K‐Akt signaling pathway; 2) downregulation of ABCB1/P‐gp to enhance the chemosensitivity of RCC to Su; and 3) reprogramming of macrophages toward M1 polarization and promotion of CD8+ T cell infiltration, thereby exerting potent antitumor activity. Abstract Renal cell carcinoma (RCC) is a malignant tumor with highly recurrent and metastatic capability. The current therapies for RCC are limited by drug resistance and toxic side effects. This study introduces an innovative approach that combines ginger‐derived exosome‐like nanoparticles (GELNs) with sunitinib (Su) and folic acid‐polyethylene glycol (FA‐PEG, FPD) in an active‐passive targeting strategy to explore its multi‐mechanism 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‐Akt signaling pathway, which is subsequently validated through in vitro experiments. By loading Su and modifying it with FPD, FPD‐GELNs/Su is constructed. The FPD modification significantly enhanced tumor targeting and amplified the Su sensitivity by reducing ABCB1/P‐gp expression induced by GELNs. In vivo experiments revealed that FPD‐GELNs/Su promoted M1 macrophage polarization and increased immune T‐cell 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‐GELNs/Su inhibits RCC progression through multiple pathways, providing new insights for the development of precise and low‐toxicity nano‐therapies. FPD-GELNs co-deliver Su and bioactive components. This active-passive dual-targeting strategy suppresses the progression of RCC through the following mechanisms: 1) inhibition of the PI3K-Akt signaling pathway; 2) downregulation of ABCB1/P-gp to enhance the chemosensitivity of RCC to Su; and 3) reprogramming of macrophages toward M1 polarization and promotion of CD8 + T cell infiltration, thereby exerting potent antitumor activity. Abstract Renal cell carcinoma (RCC) is a malignant tumor with highly recurrent and metastatic capability. The current therapies for RCC are limited by drug resistance and toxic side effects. This study introduces an innovative approach that combines ginger-derived exosome-like nanoparticles (GELNs) with sunitinib (Su) and folic acid-polyethylene glycol (FA-PEG, FPD) in an active-passive targeting strategy to explore its multi-mechanism 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-Akt signaling pathway, which is subsequently validated through in vitro experiments. By loading Su and modifying it with FPD, FPD-GELNs/Su is constructed. The FPD modification significantly enhanced tumor targeting and amplified the Su sensitivity by reducing ABCB1/P-gp expression induced by GELNs. In vivo experiments revealed that FPD-GELNs/Su promoted M1 macrophage polarization and increased immune T-cell 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-GELNs/Su inhibits RCC progression through multiple pathways, providing new insights for the development of precise and low-toxicity nano-therapies. Advanced Science, EarlyView.