In vivo Reprogramming of T Cells with LNP-Encoded CLDN18.2 CAR mRNA for Solid Tumor Eradication

This study presents a novel conceptual framework for CLDN18.2-targeted CAR-T cell therapy. The single-chain variable fragment (scFv) structure was predicted using AlphaFold2, followed by four rounds of docking simulations with HADDOCK, ultimately identifying a conformation with favorable affinity and structural stability. To enable in vivo CAR expression, three mRNA delivery systems—lipid nanoparticles (LNPs), the cationic polymer TMAB3, and peptide-coated RNACap capsules—were modeled and compared in terms of kinetic profiles, tissue tropism, and safety considerations. To improve tumor specificity and reduce systemic toxicity, transcriptional regulation elements such as NR4A2 and RGS16 promoters were conceptually introduced to confine CAR expression to the tumor microenvironment. Additionally, a chemokine-guided homing model for CD8⁺ T cells was simulated to mimic immune navigation and targeted therapeutic engagement. Collectively, this work proposes a closed-loop CAR-T system integrating in vivo mRNA delivery, tumor-specific transcriptional activation, antigen targeting, and immune cell homing. This integrative framework offers a potentially translatable strategy for improving solid tumor immunotherapy. This study is entirely based on computational modeling and publicly available biological data, without involving any human or animal subjects.