Targeting the peripheral nervous system in adipose tissue with engineered AAV vectors

Adipose tissue innervation plays a critical role in regulating energy homeostasis and metabolic functions, yet targeted gene delivery to these peripheral nerves has remained challenging. We systematically evaluated both naturally occurring and engineered adeno-associated virus (AAV) capsids for their ability to transduce nerve fibers in the adipose tissue of mice. We compared seven AAVs (AAV1, AAVrg, AAV5, AAV9, AAV-PHP.S, AAV-MaCPNS1, and AAV-MaCPNS2) in C57BL/6J mice and identified AAV-PHP.S as highly efficient for transducing nerves within inguinal subcutaneous white adipose tissue (ing-scWAT). Titration studies further optimized intra-adipose delivery to minimize off-target expression while selectively targeting adipose tissue nerves. Building on this optimization, we employed Cre-dependent AAVs to selectively target Nav1.8⁺ sensory nerves in ing-scWAT, enabling Tetbow-based multicolor axon labeling and delivery of a chemogenetic effector. Together, these findings establish conditions for AAV transgene delivery to adipose nerves, providing opportunities for mechanistic studies and the development of therapies for neuropathic disorders.