Bioactive polythioctic acid-engineered ropivacaine alleviates bone cancer pain through prolonged analgesia and multi-functional neuroprotection

Bone cancer pain (BCP), driven by tumor-induced bone destruction and central sensitization, represents a major clinical challenge. Although ropivacaine (Rop) is a cornerstone for BCP management, it fails to provide prolonged analgesia and neuroprotective benefits. Through RNA transcriptomics and phenotypic analysis in a murine model of metastatic BCP, we show that while Rop rapidly alleviates mechanical and thermal hyperalgesia, it paradoxically exacerbates spinal oxidative stress and neuroinflammation. To address this paradox, we engineered a multifunctional, redox-responsive polymer platform designed to prolong analgesia and mitigate Rop-associated neuronal injury concurrently. Leveraging polythioctic acid (PTA) with a responsive disulfide framework, the encapsulated Rop achieves a sustained release profile to facilitate prolonged analgesia under reductive tumor microenvironment. Meanwhile, the liberated thioctic acid (TA) acts as an antioxidant to ameliorate both neurotoxicity and neuroinflammation. Consequently, the PTA@Rop nanoparticle achieves a 1.6-fold extension of the analgesia window compared to free Rop in vivo , leading to preservation of bone microarchitecture and suppression of pro-inflammatory cytokine cascades. Mechanistically, transcriptomic profiling further reveals that PTA@Rop platform reshapes the spinal gene expression landscape and reduced nerve growth factor (NGF) homeostasis to suppress central sensitization. Our nanobiotechnology engineering decouples prolonged analgesia of Rop from unwanted neurotoxicity, providing proof-of-concept evidence for a mechanism-driven nanoplatform for BCP management.