# Oxidation-activated nanotherapy boosts tumor immunity and disrupts tumor-nerve crosstalk to combat bone metastases and cancer pain **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 PMC · DOI: 10.1126/sciadv.ady1292 · Science Advances · 2026-01-23 ## TL;DR A new nanotherapy halts bone metastases, relieves cancer pain, and restores bone health by modulating immune and neural circuits. ## Contribution A ROS-responsive nanoplatform that combines immune activation and neural signaling disruption to combat bone metastases and pain. ## Key findings - LipoNCs@pGSDMB achieves 94% tumor suppression in breast cancer bone metastasis models. - The nanotherapy restores VGCC expression, blocking tumor-nerve signaling and relieving pain. - Multiomics analysis identifies VGCC as a prognostic biomarker in clinical bone metastasis specimens. ## Abstract Bone metastasis remains a formidable challenge in oncology due to the interdependent triad of immunosuppression, neuropathic pain, and osteolytic destruction. Current treatments fail to holistically address these pathophysiological axes. Here, we develop a reactive oxygen species (ROS)–responsive liposomal nanoplatform (LipoNCs@pGSDMB) that codelivers a polymeric stimulator of interferon genes (STING) agonist and a gasdermin B (GSDMB) plasmid for dual neuro-immune modulation. Upon tumor-selective activation in metastatic bone niches, this nanotherapy induces STING-driven immune priming and GSDMB-mediated pyroptosis, triggering potent antitumor responses. Crucially, LipoNCs@pGSDMB restore voltage-gated calcium channel (VGCC) expression in tumor cells, a prognostic biomarker identified through multiomics analysis of clinical specimens, thereby blocking calcium-dependent neurosignaling and disrupting prometastatic tumor-nerve cross-talk. In breast cancer bone metastasis models, this approach achieves 94% tumor suppression, complete pain resolution, and efficient bone restoration. By converging oxidation-responsive nanomaterial engineering, immunomodulation, and neural circuit reprogramming, this work establishes a paradigm-shifting neuroimmunotherapy platform that dismantles the self-reinforcing metastasis niche while addressing its debilitating sequelae. A nanotherapy that reprograms immune and neural circuits halts bone metastasis, relieves cancer pain, and restores bone integrity. ## Linked entities - **Genes:** GSDMB (gasdermin B) [NCBI Gene 55876], cacnb3.S (calcium channel, voltage-dependent, beta 3 subunit S homeolog) [NCBI Gene 373616] - **Proteins:** STING1 (stimulator of interferon response cGAMP interactor 1), GSDMB (gasdermin B), cacnb3.S (calcium channel, voltage-dependent, beta 3 subunit S homeolog) - **Diseases:** breast cancer (MONDO:0004989) ## Full-text entities - **Genes:** Npepps (aminopeptidase puromycin sensitive) [NCBI Gene 19155] {aka AAP-S, MP100, Psa, goku}, Irf3 (interferon regulatory factor 3) [NCBI Gene 54131] {aka C920001K05Rik, IRF-3}, Ctsk (cathepsin K) [NCBI Gene 13038] {aka MMS10-Q, Ms10q, catK}, Ifnb1 (interferon beta 1, fibroblast) [NCBI Gene 15977] {aka IFN-beta, IFNB, If1da1, Ifb}, Acp5 (acid phosphatase 5, tartrate resistant) [NCBI Gene 11433] {aka TRACP, TRAP}, Slit1 (slit guidance ligand 1) [NCBI Gene 20562] {aka Slil1, mKIAA0813}, Atp6v0d2 (ATPase, H+ transporting, lysosomal V0 subunit D2) [NCBI Gene 242341] {aka 1620401A02Rik, V-ATPase}, Cd4 (CD4 antigen) [NCBI Gene 12504] {aka L3T4, Ly-4}, Ifng (interferon gamma) [NCBI Gene 15978] {aka IFN-g, If2f, Ifg}, Sting1 (stimulator of interferon response cGAMP interactor 1) [NCBI Gene 72512] {aka 2610307O08Rik, ERIS, MPYS, Mita, STING, STING-beta}, Pthlh (parathyroid hormone-like peptide) [NCBI Gene 19227] {aka PLP, PTH-like, Pthrp}, Foxp3 (forkhead box P3) [NCBI Gene 20371] {aka JM2, scurfin, sf}, STING1 (stimulator of interferon response cGAMP interactor 1) [NCBI Gene 340061] {aka ERIS, MITA, MPYS, NET23, SAVI, STING}, Il1b (interleukin 1 beta) [NCBI Gene 16176] {aka IL-1beta, Il-1b}, Hmgb1 (high mobility group box 1) [NCBI Gene 15289] {aka HMG-1, Hmg1, SBP-1, p30}, Mmp9 (matrix metallopeptidase 9) [NCBI Gene 17395] {aka B/MMP9, Clg4b, Gel B, MMP-9, pro-MMP-9}, Fos (Fos proto-oncogene, AP-1 transcription factor subunit) [NCBI Gene 14281] {aka D12Rfj1, c-fos, cFos}, Mki67 (antigen identified by monoclonal antibody Ki 67) [NCBI Gene 17345] {aka D630048A14Rik, Ki-67, Ki67}, Trpv1 (transient receptor potential cation channel, subfamily V, member 1) [NCBI Gene 193034] {aka OTRPC1, TRPV1alpha, TRPV1beta, VR-1, Vr1}, Gapdh (glyceraldehyde-3-phosphate dehydrogenase) [NCBI Gene 14433] {aka Gapd}, Anxa5 (annexin A5) [NCBI Gene 11747] {aka Anx5, CPB-I}, Tff2 (trefoil factor 2 (spasmolytic protein 1)) [NCBI Gene 21785] {aka SP, mSP}, Bdnf (brain derived neurotrophic factor) [NCBI Gene 12064], Cd86 (CD86 antigen) [NCBI Gene 12524] {aka B7, B7-2, B7.2, B70, CLS1, Cd28l2}, Sell (selectin, lymphocyte) [NCBI Gene 20343] {aka CD62L, L-selectin, LAM-1, LECAM-1, LECAM1, Lnhr}, Cxcl10 (C-X-C motif chemokine ligand 10) [NCBI Gene 15945] {aka C7, CRG-2, INP10, IP-10, IP10, Ifi10}, Ngf (nerve growth factor) [NCBI Gene 18049] {aka Ngfb, beta-NGF}, Tac1 (tachykinin 1) [NCBI Gene 21333] {aka 4930528L02Rik, NK-1, NK1, Nkna, PPT-A, PPTA}, Calca (calcitonin/calcitonin-related polypeptide, alpha) [NCBI Gene 12310] {aka CA, CGRP-1, CGRP1, Calc, Calc1, Cgrp}, Cd247 (CD247 antigen) [NCBI Gene 12503] {aka 4930549J05Rik, A430104F18Rik, Cd3, Cd3-eta, Cd3-zeta, Cd3h}, Il18 (interleukin 18) [NCBI Gene 16173] {aka Igif, Il-18}, Tnfsf11 (tumor necrosis factor (ligand) superfamily, member 11) [NCBI Gene 21943] {aka Ly109l, ODF, OPGL, RANKL, Trance}, Cd80 (CD80 antigen) [NCBI Gene 12519] {aka B71, Cd28l, Ly-53, Ly53, MIC17, TSA1}, Cd44 (CD44 antigen) [NCBI Gene 12505] {aka HERMES, Ly-24, Pgp-1}, Gzma (granzyme A) [NCBI Gene 14938] {aka Ctla-3, Ctla3, Hf, Hf1, SE1, TSP-1}, Itgax (integrin alpha X) [NCBI Gene 16411] {aka Cd11c, Cr4, N418}, Nfatc1 (nuclear factor of activated T cells, cytoplasmic, calcineurin dependent 1) [NCBI Gene 18018] {aka 2210017P03Rik, NF-ATc, NFAT2, NFATc, Nfatcb}, Tbk1 (TANK-binding kinase 1) [NCBI Gene 56480] {aka 1200008B05Rik} - **Diseases:** bone (MESH:D001847), Bone metastases (MESH:D009362), LLC (MESH:D018827), weight loss (MESH:D015431), cold allodynia (MESH:D006930), hepatic dysfunction (MESH:D008107), Pain (MESH:D010146), osteoclast (MESH:D001862), hypersensitivity (MESH:D004342), inflammatory (MESH:D007249), breast cancer (MESH:D001943), fractures (MESH:D050723), osteolytic destruction (MESH:D008105), cancer pain (MESH:D000072716), neuroinflammation (MESH:D000090862), addiction (MESH:D019966), Cancer (MESH:D009369), chronic pain (MESH:D059350), lung cancer (MESH:D008175), artery (MESH:D012078), osteolysis (MESH:D010014), bone cancer (MESH:D001859), neuropathic (MESH:D009437), pancreatic, prostate, gastric, and brain cancers (MESH:D013274) - **Chemicals:** penicillin (MESH:D010406), wortmannin (MESH:D000077191), Triton X-100 (MESH:D017830), PFA (MESH:C003043), osmium tetroxide (MESH:D009993), Polymer (MESH:D011108), streptomycin (MESH:D013307), propidium iodide (MESH:D011419), ethanol (MESH:D000431), Acetone (MESH:D000096), Cy5 (MESH:C085321), CHEMS (MESH:C013440), ATP (MESH:D000255), ROS (MESH:D017382), carbon dioxide (MESH:D002245), Crystal violet (MESH:D005840), insulin (MESH:D007328), sodium pentobarbital (MESH:D010424), filipin (MESH:D005372), norepinephrine (MESH:D009638), CCK-8 (MESH:D012844), H2O2 (MESH:D006861), KCl (MESH:D011189), isoflurane (MESH:D007530), Calcium (MESH:D002118), gold (MESH:D006046), lipid (MESH:D008055), glutaraldehyde (MESH:D005976), N (MESH:D009584), chlorpromazine (MESH:D002746), cytochalasin D (MESH:D015638), acetylcholine (MESH:D000109), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine N-[methoxy(polyethylene glycol)-2000] (MESH:C519184), 4',6-diamidino-2-phenylindole (MESH:C007293), 5-ethynyl-2'-deoxyuridine (MESH:C031086), DAMPS (MESH:C116255), DiI (-), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (MESH:C020888), P (MESH:D010758), phenylboronate (MESH:C010686) - **Species:** Rattus norvegicus (brown rat, species) [taxon 10116], Mus musculus (house mouse, species) [taxon 10090], Homo sapiens (human, species) [taxon 9606] - **Mutations:** H to K, Q to T, G to I, L to N, U to W, N to Q - **Cell lines:** LLC — Mus musculus (Mouse), Malignant tumors of the mouse pulmonary system, Cancer cell line (CVCL_4358), OPSA — Homo sapiens (Human), Human papillomavirus-related endocervical adenocarcinoma, Cancer cell line (CVCL_1906), 4 T1 — Mus musculus (Mouse), Malignant neoplasms of the mouse mammary gland, Cancer cell line (CVCL_0125), 4T1-Luc — Mus musculus (Mouse), Malignant neoplasms of the mouse mammary gland, Cancer cell line (CVCL_J239), NK92 — Homo sapiens (Human), Natural killer cell lymphoblastic leukemia/lymphoma, Cancer cell line (CVCL_2142), /c — Mus musculus (Mouse), Hepatocellular carcinoma of the mouse, Cancer cell line (CVCL_9103), Balb/c — Mus musculus (Mouse), Spontaneously immortalized cell line (CVCL_0184) ## Full text _Full body text omitted from this summary view._ Fetch the complete paper as Markdown: https://tomesphere.com/paper/PMC12829578/full.md ## Figures 7 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12829578/full.md ## References 76 references — full list in the complete paper: https://tomesphere.com/paper/PMC12829578/full.md --- Source: https://tomesphere.com/paper/PMC12829578