Neurotransmitter-endcapped poly(β-amino estate) for enhanced DNA delivery to the brain through intravenous injection

While nonviral gene delivery systems have achieved clinical success, targeted delivery remains critical for safety and broader applications of gene therapy. Conventional targeting approaches often compromise efficacy due to synthetic complexity or formulation instability. Hyperbranched poly(β-amino ester)s (HPAEs), as a novel type of gene delivery vector, offer superior functionalization potential via their abundant terminal groups. Here, we conjugate tryptamine with acrylate groups of the HPAE backbone through Michael addition, enabling brain-specific targeting with precise control over HPAE terminal composition. This modification enhanced transfection efficacy by 2-3-fold in glioma cells versus unmodified HPAEs. We further designed a Smart Core-Shell (SCS) polyplex formulation strategy by using unmodified HPAEs as the plasmid DNA encapsulation core, along with tryptamine-modified HPAEs as the coating shell through simple mixing in the dilution buffer. The SCS strategy synergized gene entrapment with targeting capabilities, demonstrating significantly enhanced transfection efficacy in brain cells while reducing tryptamine consumption by 30-60 %. Furthermore, in vivo studies confirmed trans-blood-brain barrier delivery and reporter pDNA expression in the brain by the tryptamine-modified HPAEs based polyplex. This rational HPAE formulation maximizes functional end-group accessibility, minimizes synthetic redundancy and nanoparticle instability, and establishes generalized principles for engineering high-performance polymeric vectors with enhanced functionality and manufacturing practicality.