The on-demand administration of anaesthetic drugs can be a promising alternative for chronic pain management. To further improve the efficacy of drug delivery vectors, high drug loadings combined with a spatiotemporal control on the release can not only relief the pain according to patient’s needs, but also improve the drawbacks of conventional burst release delivery systems. In this study, a hybrid nanomaterial was developed by loading bupivacaine nanocrystals (BNCs) into oligo(ethylene glycol) methyl ether methacrylate (OEGMA)-based thermoresponsive nanogels and coupling them to NIR-absorbing biodegradable copper sulphide nanoparticles (CuS NPs). Those CuS NPs were surface modified with polyelectrolytes using layer-by-layer techniques to be efficiently attached to the surface of nanogels by means of supramolecular interactions. The encapsulation of bupivacaine in the form of nanocrystals allowed to achieve CuS@BNC-nanogels having drug loadings as high as 65.5 wt%. The nanocrystals acted as long-lasting drug reservoirs, leading to an elevated localized drug content, which was useful for their application in prolonged pain relief. The CuS@BNC-nanogels exhibited favorable photothermal transducing properties upon NIR-light irradiation. The photothermal effect granted by the CuS NPs triggered the nano-crystallized drug release to be boosted by the collapse of the thermoresponsive nanogels upon heating. Remote control was achieved for on-demand release at a specific time and place, indicating their potential use as an externally activated triggerable drug-delivery system. Furthermore, cell viability tests and flow cytometry analysis were performed showing satisfactory cytocompatibility in the dose-ranging study having a subcytotoxic concentration of 0.05 mg/mL for CuS@BNC-nanogels. This remotely activated nanoplatform is a promising strategy for long-lasting controlled analgesia and a potential alternative for clinical pain management.

麻醉药物的按需给药可能是慢性疼痛管理的一个有前途的替代方案。为了进一步提高给药载体的疗效，高载药量结合释放的时空控制，不仅可以根据患者的需要缓解疼痛，还可以改善传统突释给药系统的缺点。在这项研究中，通过将布比卡因纳米晶体 (BNCs) 加载到基于低聚 (乙二醇) 甲基醚甲基丙烯酸酯 (OEGMA) 的热响应纳米凝胶中，并将它们与吸收 NIR 的可生物降解硫化铜纳米颗粒 (CuS NPs) 偶联，开发了一种混合纳米材料。这些 CuS NPs 使用聚电解质进行表面改性，使用逐层技术通过超分子相互作用有效地附着在纳米凝胶的表面。以纳米晶体形式包封布比卡因可以实现载药量高达 65.5% 的 CuS@BNC-纳米凝胶。纳米晶体充当持久的药物储库，导致局部药物含量升高，这有助于它们在长期镇痛中的应用。CuS@BNC-纳米凝胶在近红外光照射下表现出良好的光热转换性能。CuS NPs 赋予的光热效应触发了纳米结晶药物的释放，通过加热时热响应纳米凝胶的坍塌来促进纳米晶化药物的释放。在特定时间和地点实现了按需释放的远程控制，表明它们作为外部激活的可触发给药系统的潜在用途。此外，进行了细胞活力测试和流式细胞术分析，在剂量范围研究中显示出令人满意的细胞相容性，CuS@BNC-纳米凝胶的亚细胞毒性浓度为 0.05 mg/mL。这种远程激活的纳米平台是一种有前途的长期受控镇痛策略，也是临床疼痛管理的潜在替代方案。