Harnessing synaptic vesicle release and recycling with antibody shuttle for targeted delivery of therapeutics to neurons

The effective delivery of therapeutic molecules to neurons are mainly limited by the presence of the blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB), leading to suboptimal therapeutic outcomes in neurodegenerative diseases treatment. This study introduces a neuron-selective drug delivery system that utilizes the synaptic vesicle release and recycling mechanism (SVRM) to overcome these barriers. This delivery system consists of an antibody shuttle that targets SV transmembrane proteins, which enables selective molecule delivery to neurons. We demonstrated that intravenously administered antibodies raised against the luminal domain of synaptotagmin-2 (SYT2) selectively localize to neuromuscular junctions. They were taken up and retrogradely transported to CHAT-positive motor neurons in both the spinal cord and brainstem. Anti-SYT2 antibody delivery of anti-microtubule agent and <i>MALAT1</i> gapmer antisense oligonucleotides (ASOs) induces axonal degeneration and <i>MALAT1</i> RNA downregulation <i>in vitro</i>, respectively. Additionally, intravenous administration of anti-SYT2 conjugated with <i>MALAT1</i> gapmer ASOs in mice resulted in the reduction of <i>Malat1</i> RNA in targeted cells. This approach circumvents the BSCB, enabling the neuron-selective delivery of therapeutic agents to increase neuronal drug concentrations while minimizing off-target effects in non-targeted cells. Thus, harnessing the SVRM offers a promising strategy to enhance the therapeutic index for neurodegenerative diseases treatment.