Synergistic inhibition of exosome secretion and PD-L1 silence via a functional supramolecular lipid nanoparticle to boost antitumor immunity.

Abstract

The treatment of malignancies remains a formidable challenge, driven by the complex interplay of exosome-mediated metastasis and PD-L1-driven immune evasion. Overcoming these barriers through simultaneous modulation of both pathways represents a critical, yet unmet, need in cancer therapy. To address this, we engineer a supramolecular lipid nanoparticle (LNP) wherein lipid-modified cyclodextrin and oxaliplatin (OxPt-2PA) synergize as both a delivery vector and an immunogenic cell death inducer. Leveraging multiple supramolecular interactions, this platform co-encapsulates the exosome inhibitor Nexinhib20 and small interfering RNA targeting PD-L1 (siPD-L1), orchestrating a multi-pronged attack on tumor progression and immunosuppression. In vivo, this therapeutic strategy markedly enhances dendritic cell maturation, promotes cytotoxic T cell infiltration and significantly suppresses both primary tumor growth and distant metastasis. This work establishes a chemotherapy-induced supramolecular integrated co-delivery platform that simultaneously counteracts metastasis and immunosuppression via "drug-and-gene" therapy, offering a promising strategy for the treatment of aggressive cancer.