Abstract: Prostheses have a several thousand year history for treating limb loss. With time, these prostheses have become more sophisticated and closer to replicating the natural limb. These advances have culminated in the myoelectrically controlled prosthesis, which employs the surface electromyogram to decode the user’s intent. But the surface electromyogram lacks fidelity and though convenient, suffers from several problems. The skin-electrode interface undergoes impedance changes throughout the day and electrode liftoff can cause signal loss. A better solution would be to interface directly with the residual nerves which still carry the descending and ascending neural impulses. Signals can be recorded through electrodes implanted within peripheral nerves or the spinal cord, however current electrode technologies generally trade specificity for longevity and reliability. Electrodes that have high specificity use penetrating approaches that often irritate, damage and become encapsulated with fibrotic tissue limiting their long term viability (see (Navarro et al., 2005) for a review of surface electromyogram and electrode based interfaces). Optical approaches may obviate this problem and provide high specificity with limited invasiveness. Through the use of optogenetic actuator and reporter proteins, an optogenetic peripheral nerve interface can circumvent these problems by using light to manipulate and detect neural activity. This interface could be deployed for both prosthesis control following limb loss or limb reanimation following spinal cord injury (for example, see optogenetic actuation in a nonhuman primate model by (Williams et al., 2019)). An additional advantage of using optogenetic actuators in limb reanimation is that they may have a more physiologic motor unit recruitment pattern, recruiting slow oxidative fibers at lower stimulus than fast glycolytic fibers, reducing fatigue compared to electrical stimulation which recruits larger fibers at lower stimulus (Llewellyn et al., 2010). As transgenes, these optogenetic proteins require a method of delivery to the nerve, which can be achieved using viral vectors, which offer a high transduction efficiency. Of these vectors, adenoassociated viral vectors (AAVs) are particularly interesting because they are relatively nonimmunogenic and have been approved by the United States Food and Drug Administration to treat several genetic diseases. Furthermore, unlike lentiviruses and their wild-type progenitors, AAVs rarely integrate into the host genome, yet still provide extended expression. Targeting of these vectors to the motor and sensory neurons, and ultimately the axons of the dorsal root ganglia and ventral horn of the spinal cord is critical. Off-target expression can cause toxicity and immunogenicity. Selectivity is achieved through route of administration, expression cassette design, and serotype selection and capsid engineering (Figure 1A).