Dendrimer-based nanoplatforms for enhanced mRNA delivery: From rational structural design to formulation strategies

• Dendrimer modification strategies for enhanced gene delivery are discussed. • Dendrimer-based nanoformulations boosting gene delivery are summarized. • Ionizable amphiphilic Janus dendrimers in mRNA delivery are reviewed. • Recent applications of dendrimer-mediated mRNA delivery are reviewed. • Future challenges and developments in dendrimer mRNA therapeutics are addressed. Development of safe and efficient mRNA delivery systems remains challenging. Dendrimers have emerged as promising mRNA carriers due to their unique advantages, including high nucleic acid condensation efficiency, nuclease protection capability, enhanced cellular uptake and endosomal escape capability mediated by proton sponge effect. However, their clinical applications are often limited by cytotoxicity and suboptimal size. Surface functionalization strategies, including targeting ligand modification or polyethylene glycol modification, can effectively mitigate their cytotoxicity while improving bioavailability and circulation stability. Furthermore, to address rapid systemic clearance of small-sized dendrimers, advanced nanostructures such as nanoclusters, core-shell tecto dendrimers, nanogels, and hybrid systems have been developed to enhance the gene delivery efficiency. Ionizable amphiphilic Janus dendrimers are also promising materials for mRNA delivery applications. This review systematically examines mRNA therapeutic applications in gene editing, cancer therapy, anti-inflammation therapy and infectious disease treatment using dendrimer-based vectors. Current challenges and future directions for optimizing dendrimer-based mRNA therapeutics are also briefly discussed.