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Background Autologous CAR-T cell therapies have demonstrated remarkable efficacy in hematologic malignancies and are showing promise in treating autoimmune diseases (AID) driven by pathogenic B cells. However, their clinical adoption remains limited due to complex manufacturing, the need for lymphodepletion, and high costs.Methods To address these limitations, we developed a T cell-targeted lipid nanoparticle (T-LNP) system for in vivo CAR-T reprogramming. Enabled by our proprietary CLAMP (Controllable Ligand Attachment Modification and Purification) technology, this system allows precise, site-specific antibody conjugation to LNPs. This design maximizes binder efficiency, allowing effective targeting with minimal ligand input. Importantly, the CLAMP platform is fully compatible with large-scale LNP manufacturing and purification workflows.Results In combination with optimized mRNA chemistry, the T-LNP platform enables robust and sustained CAR expression in human PBMC, persisting for over 10 days in vitro. In human PBMC-transplanted NOG mice, a single intravenous dose as low as 0.01 mg/kg achieved >95% B cell clearance. The engineered hinge design and stealth-layer design minimized off-target uptake by monocytes, macrophages, and dendritic cells to below 5%. By selectively targeting T cell markers, the system achieved >90% CAR expression and promoted >30-fold expansion in vivo. The LNP formulation incorporates proprietary ionizable lipids with favorable pharmacokinetics and safety profiles across species. Minimal cytokine release (IL-6, TNF-α) following administration supports this formulation’s safety and suitability for repeated dosing.Conclusions These findings demonstrate that our T-LNP platform enables efficient, targeted, and sustained in vivo CAR expression with a favorable safety profile and scalable manufacturing. A clinical batch is currently in production, with a first-in-human investigator-initiated trial (IIT) in China expected to launch soon.