Spatiotemporally tunable analgesic depot for on-demand postoperative pain management

Effective postoperative pain management remains a major clinical challenge. Local anesthetics are preferred for their safety and efficacy, but their short duration of action necessitates repeated administrations, leading to fluctuating analgesia and patient discomfort. Current extended-release formulations extend analgesic duration but cannot dynamically respond to evolving pain states or sustain the high drug concentrations required during acute phases. While hydrophilic gels provide rapid pain relief via the quick release of small-molecule anesthetics, premature reservoir depletion often compromises long-term analgesia. Here, inspired by the dual pharmaceutical forms of hydrophilic salts and hydrophobic bases, we develop a spatiotemporally programmable analgesic depot that integrates rapid-onset and prolonged-release capabilities within one system. The platform combines a hydrophilic hydrogel for instantaneous release of ropivacaine hydrochloride (RH) with hydrophobic short poly(L-lactic acid) (SPLLA) nanofibers for sustained delivery of ropivacaine base (RB). Moreover, external ultrasound (US) enables non-invasive, on-demand regulation of release kinetics. In a rat incisional pain model, this dual-phase depot achieved rapid analgesia (83.3% mechanical threshold recovery at 3 h) and prolonged efficacy, accompanied by reduced c-Fos⁺/TRPV1⁺ neuronal activation and no detectable tissue toxicity. This strategy reconciles the conflicting demands of fast-acting and long-lasting anesthesia, offering a promising non-opioid approach for adaptive and long-duration postoperative pain management.