Grapefruit Extracellular-Vesicle-Derived Nanodrug Loading Three-Functional Platinum(IV) Conjugates with Enhanced Targeting and TME Modulating Properties

Grapefruit extracellular vesicle (GEVs) derived nanodrug Tf-GEVs@Pt(IV) loading novel three-functional platinum(IV) conjugates was developed, which was effective in modulating the inflammatory, fibrotic, and immunosuppressive tumor microenvironment (TME). The GEVs enhanced the penetration of Tf-GEVs@Pt(IV) into tumor tissues, while the transferrin (Tf) moiety further improved the tumor-targeting capabilities. The active ingredient, platinum(IV) conjugate, was released in a sustained manner within the TME, which was easily reduced to platinum(II), aspirin (ASP), and captopril (CTP) fragments. The platinum core caused significant DNA damage. The inflammatory TME was ameliorated by inhibiting COX-2 and reducing TNF-α and IL-6 through the synergistic actions of GEVs and ASP. Collagen fibrosis was disrupted by the CTP moiety, which downregulated TGF-β1, MMP2, and MMP9. Consequently, the immunologically ‘cold’ TME was transformed into a ‘hot’ state by inhibiting PD-L1 and activating cGAS/STING pathways. Then, the T-cell activation and macrophage polarization from the M2- to M1-phenotype were provoked in tumor tissues.