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Bone metastasis presents core challenges of immunosuppression, neuropathic pain, and osteolysis that are mutually dependent. Current treatments are unable to comprehensively cover these pathological physiological axes. This study constructed reactive lipidosome nanoplatforms of reactive oxygen species (ROS), which simultaneously delivered STING agonists and GSDMB plasmids to achieve dual neuro-immune regulation. After being selectively activated by tumors at the metastatic bone sites, this platform can induce STING-driven immune activation and GSDMB-mediated apoptosis, while restoring the expression of VGCC as a prognostic biomarker and blocking calcium-dependent neural signals to disrupt the tumor-neural interaction, establishing a novel neuro-immune therapy platform that provides an effective solution for dismantling the metastatic niche. Research Background
Bone metastasis is an important unsolved problem in oncology. Its key pathological feature lies in the complex network formed by immunosuppression, neuropathic pain, and osteolysis. Current treatment methods can only intervene in a single pathological link and cannot comprehensively regulate these interrelated pathological physiological axes. Therefore, it is urgent to develop innovative treatment strategies that can simultaneously address multiple problems.
Main content
The core of this study is to develop the ROS-responsive lipid nanoparticle nanodelivery system (LipoNCs@pGSDMB), which achieves dual neuro-immune regulatory effects by co-delivering STING agonists and GSDMB plasmids. This system has tumor-selective activation characteristics and functions specifically at metastatic bone sites: on the one hand, it induces STING-driven immune activation and GSDMB-mediated apoptosis, triggering a powerful anti-tumor response; on the other hand, it restores the expression of VGCC in tumor cells - this marker has been verified by multi-omics analysis of clinical samples, thereby blocking calcium-dependent neural signal transduction and destroying the interaction between metastatic tumors and nerves at the mechanism level.
Research design
First, a ROS-responsive lipid nanoparticle platform was constructed, and the design for co-loading and targeted delivery of STING agonists and GSDMB plasmids was completed; through multi-omics analysis of clinical samples, the value of voltage-gated calcium channel (VGCC) as a prognostic biomarker was screened and verified; using a breast cancer bone metastasis model as the research carrier, the mechanism and biological effects of this nanotherapy in immune activation, apoptosis induction, neural signal blockade, tumor regulation, and bone repair were systematically explored. Result
This nanotherapy successfully triggered a potent anti-tumor response, effectively disrupting the interaction between metastatic tumors and nerves, achieving pain relief and bone repair, and successfully dismantling the self-reinforcing metastatic niche and related sequelae in bone metastasis, verifying the effectiveness of the dual neural immune regulation strategy.
Thought extension
This study innovatively integrates oxide-responsive nanomaterial engineering, immune regulation mechanisms, and neural circuit reprogramming technology, breaking through the limitations of traditional single-target treatment and establishing a paradigm-shifting neural immune therapy platform. Its core idea is to simultaneously intervene in the immunosuppressive microenvironment of bone metastasis, the tumor-neuron interaction pathway, and the process of bone destruction through multiple mechanisms, providing a new research perspective and technical framework for solving the complex tumor metastasis problem involving multiple pathological links.
Original source:
Authors: Zhaowei Zhang, Pengfei Chen, Yufei Zheng, Mobai Li, Lan Zhao, Zezhou Fu, Yujie Zhou, Tingyu Zhang, Xuanrong Sun, Dingcheng Zhu, Youqing Shen, Shunwu Fan, Xin Liu, Jiajia Xiang. Publication Date: January 23, 2026. DOI: 10.1126/sciadv.ady1292. Journal: ACS Nano
