Local analgesia is a prevalent and cost-effective pain management strategy with minimal systemic side effects. At the same time, nanotechnology has been employed to achieve the sustained release of drugs to prolong the duration of local anesthetics (LAs). However, these traditional nanoformulations lack responsiveness and thus cannot achieve precise pain relief through on-demand administration. The emergence of “intelligent” nanosystems with stimulus-response capabilities has opened up new prospects in pain control. This review summarizes recent advancements in the design and application of triggerable LAs nanoformulations that can be activated by external stimuli such as light, ultrasound, or heat. These systems facilitate precise, patient-specific pain management, transforming the clinical approach from long-term suppression to controllable and on-demand relief. Finally, we discussed the current challenges and future prospects. A deeper understanding of this field will facilitate the development of superior analgesic solutions and ultimately improve the treatment outcomes for patients.

Background/Objectives: The clinical management of visceral pain remains a significant challenge. Our previous study confirmed the analgesic efficacy of dexmedetomidine (Dex) in a mouse model of inflammatory visceral pain (IVP). However, the underlying molecular mechanism, particularly regarding immune regulation, has not been fully elucidated. Methods: In the present study, transcriptomic profiling of both physiological and disease states was performed to characterize associated molecular and immune signatures. Key driver genes were identified by integrating differentially expressed genes (DEGs) from the IVP model with potential Dex targets derived from network pharmacology. Molecular docking simulations evaluated binding interactions. The correlations between Dex’s targets and immune cell infiltration patterns, with a focus on macrophages, were analyzed. Results: Multi-tissue analysis revealed a strong association between IVP pathogenesis and pro-inflammatory immune responses, specifically a shift in macrophage polarization. Within this dysregulated network, seven proteins were identified as direct potential targets of Dex. Among these, six core targets, such as ADGRF1, IDO1, JAK3 and NR1H4, demonstrated the most significant correlations with M1-like macrophages and exhibited strong in silico binding potential with Dex. Conclusions: This integrated analysis suggests that Dex may alleviate visceral pain by modulating a specific gene network linked to pro-inflammatory macrophage activation, thereby promoting the restoration of immune balance. Our findings provide a novel mechanism-informed perspective for the application of Dex in visceral pain therapy.