Internalizing RGD (iRGD)-modified liposomal nanoparticles as a universal antigen-delivering platform for remodeling...

T cell receptor-engineered T cell (TCR-T) therapy holds promise for solid tumors but faces challenges from insufficient and non-uniform antigen presentation and inefficient T-cell tumor delivery. Current strategies that rely on endogenous tumor antigen expression are often limited by transcriptional silencing or downregulation of target antigens in a substantial fraction of tumor cells, resulting in incomplete tumor recognition. To address this, we developed iRGD-modified liposomal nanoparticles (iRNY-LNPs) as a universal antigen-delivering platform for remodeling tumors and enhancing TCR-T immunotherapy. The iRNY-LNPs, co-assembled from DSPE-PEG-iRGD and DSPE-PEG-NY-ESO-1 (New York Esophageal Squamous Cell Carcinoma-1), exhibited a uniform size of 206.3 ± 5.4 nm and demonstrated significantly enhanced penetration into 3D tumor spheroids compared to non-targeted nanoparticles. In vitro, iRNY-LNPs enabled uniform NY-ESO-1 antigen presentation on tumor cells, potently activating TCR-T cells and enhancing interferon-γ secretion and cytotoxicity. In vivo imaging confirmed efficient tumor accumulation and retention of iRNY-LNPs. In a gastric cancer model, the combination of iRNY-LNPs and NY-ESO-1 TCR-T cells achieved 73.0% tumor growth inhibition and significantly prolonged survival, with no observed systemic toxicity. This study establishes a proactive tumor-remodeling strategy that circumvents the reliance on endogenous antigen expression by enforcing uniform antigen display. Given its modular design based on lipid-peptide conjugates, the platform can be readily adapted to deliver other tumor-associated antigens by simply substituting the peptide moiety, offering a versatile framework for TCR-T immunotherapy against diverse solid tumors.