Protein Nanocages Enable Programmable and Targeted mRNA Delivery

The clinical efficacy of mRNA therapeutics is governed by precise cellular targeting and tuneable control, both of which critically depend on the spatiotemporal efficiency of mRNA delivery platforms. However, achieving atomically precise customization and genetically encoded architectural control, hallmarks of biomolecular engineering, remains challenging for conventional platforms such as lipid nanoparticles (LNPs). Here, we present the Protein Cage-enabled Targeted RNA Delivery (PCT-RD) platform, a genetically encoded protein nanocage that self-assembles in Escherichia coli and enables programmable mRNA copackaging through engineered lambdaN+-boxB RNA-protein recognition. The pH-responsive GALA domain facilitates endosomal escape and cytosolic release, whereas structure-guided evolution enhances mRNA encapsulation fidelity. Surface-displayed nanobody ligands or albumin-binding peptides enable cell-specific targeting and extended systemic circulation. Using this platform, we achieved programmable delivery of therapeutic mRNAs encoding anti-PD1 antibodies and a fifth-generation CD19-targeting chimeric antigen receptor (CAR) for in vivo cell reprogramming. PCT-RD allows for in situ CAR-T-cell generation, sustains therapeutic antibody expression, and elicits potent antitumour responses in both solid tumours and haematological malignancies. This study establishes PCT-RD as a genetically encoded, scalable, and versatile alternative to LNPs for next-generation mRNA therapeutics.