Preserved motor function and prolonged sensory local anesthesia with novel PLGA microparticles co-encapsulating lidocaine and capsaicin

Lidocaine (LID) provides rapid local anesthesia but lacks nerve-type selectivity, causing undesired motor impairment, and typically suffers from a rapid washout effect. To address these acute-phase limitations, we developed biodegradable poly (lactic-co-glycolic acid) (PLGA) microparticles co-encapsulating LID and capsaicin (CAP), a transient receptor potential vanilloid 1 (TRPV1) agonist. CAP facilitates TRPV1 channel opening exclusively in sensory nerve C-fibers, allowing selective LID internalization. In vivo functional efficacy was assessed during a critical 60-min acute phase using rotarod testing and electrophysiological recordings of the saphenous nerve in the mice. While LID monotherapy caused significant motor coordination deficits and exhibited rapid dissipation of the sensory blockade within 30 min, CAP co-encapsulation successfully overcame both of these issues. Motor impairment was reduced to approximately 6-8% of that observed with lidocaine-loaded PLGA microparticles without capsaicin, preserving near-normal motor function. An electrophysiological analysis demonstrated a rapid onset of action and complete prevention of early washout, sustaining profound suppression of sensory nerve activity throughout the 60-min observation period. These findings provide compelling physiological proof-of-concept that our PLGA-based co-delivery strategy achieves rapid-onset, functionally sensory-selective, and extended acute local anesthesia. This innovative system demonstrates a strong translational potential for improving postoperative pain management and early functional recovery.