[1] [1] Skolnick P. The opioid epidemic: crisis and solutions. Annu Rev Pharmacol Toxicol. 2018;58:143.10.1146/annurev-pharmtox-010617-052534

[2] [2] Zhang WJ, Ning C, Xu W, Hu H, Li MQ, Zhao GQ, Ding JX, Chen XS. Precision-guided long-acting analgesia by gel-immobilized bupivacaine-loaded microsphere. Theranostics. 2018;8:3331.10.7150/thno.25276

[3] [3] Macfarlane AJR, Gitman M, Bornstein KJ, El-Boghdadly K, Weinberg G. Updates in our understanding of local anaesthetic systemic toxicity: a narrative review. Anaesthesia. 2021;76(Suppl 1):27.10.1111/anae.15282

[4] [4] Zhang QS, Ren YM, Mo YQ, Guo PP, Liao P, Luo YC, Mu J, Chen Z, Zhang Y, Li Y, Yang LH, Liao DQ, Fu J, Shen JW, Huang W, Xu XW, Guo YY, Mei LH, Zuo YX, Liu J, Yang HY, Jiang RT. Inhibiting Hv1 channel in peripheral sensory neurons attenuates chronic inflammatory pain and opioid side effects. Cell Res. 2022;32:461.10.1038/s41422-022-00616-y

[5] [5] Shen HZ, Liu DL, Wu K, Lei JL, Yan NE. Structures of human Na(v)1.7 channel in complex with auxiliary subunits and animal toxins. Science. 2019;363:1303.10.1126/science.aaw2493

[6] [6] Osteen JD, Herzig V, Gilchrist J, Emrick JJ, Zhang CC, Wang XD, Castro J, Garcia-Caraballo S, Grundy L, Rychkov GY, Weyer AD, Dekan Z, Undheim EA, Alewood P, Stucky CL, Brierley SM, Basbaum AI, Bosmans F, King GF, Julius D. Selective spider toxins reveal a role for the Nav1.1 channel in mechanical pain. Nature. 2016;534:494.10.1038/nature17976

[7] [7] Binshtok AM, Bean BP, Woolf CJ. Inhibition of nociceptors by TRPV1-mediated entry of impermeant sodium channel blockers. Nature. 2007;449:607.10.1038/nature06191

[8] [8] Xu ZZ, Kim YH, Bang SS, Zhang Y, Berta T, Wang F, Oh SB, Ji RR. Inhibition of mechanical allodynia in neuropathic pain by TLR5-mediated A-fiber blockade. Nat Med. 2015;21:1326.10.1038/nm.3978

[9] [9] Zhang Q, Luo P, Xia F, Tang H, Chen JY, Zhang JZ, Liu DD, Zhu YP, Liu YQ, Gu LW, Zheng LH, Li ZJ, Yang F, Dai LY, Liao FL, Xu CC, Wang JA. Capsaicin ameliorates inflammation in a TRPV1-independent mechanism by inhibiting PKM2-LDHA-mediated Warburg effect in sepsis. Cell Chem Biol. 2022;29:1248.10.1016/j.chembiol.2022.06.011

[10] [10] Liao MF, Cao EH, Julius D, Cheng YF. Structure of the TRPV1 ion channel determined by electron cryo-microscopy. Nature. 2013;504:107.10.1038/nature12822

[11] [11] Zhang KH, Julius D, Cheng YF. Structural snapshots of TRPV1 reveal mechanism of polymodal functionality. Cell. 2021;184:5138.10.1016/j.cell.2021.08.012

[12] [12] Blake KJ, Baral P, Voisin T, Lubkin A, Pinho-Ribeiro FA, Adams KL, Roberson DP, Ma YC, Otto M, Woolf CJ, Torres VJ, Chiu IM. Staphylococcus aureus produces pain through pore-forming toxins and neuronal TRPV1 that is silenced by QX-314. Nat Commun. 2018;9:37.10.1038/s41467-017-02448-6

[13] [13] Arora V, Campbell JN, Chung MK. Fight fire with fire: neurobiology of capsaicin-induced analgesia for chronic pain. Pharmacol Ther. 2021;220: 107743.10.1016/j.pharmthera.2020.107743

[14] [14] Ries CR, Pillai R, Chung CC, Wang JT, MacLeod BA, Schwarz SK. QX-314 produces long-lasting local anesthesia modulated by transient receptor potential vanilloid receptors in mice. Anesthesiology. 2009;111:122.10.1097/ALN.0b013e3181a9160e

[15] [15] Stueber T, Eberhardt MJ, Hadamitzky C, Jangra A, Schenk S, Dick F, Stoetzer C, Kistner K, Reeh PW, Binshtok AM, Leffler A. Quaternary lidocaine derivative QX-314 activates and permeates human TRPV1 and TRPA1 to produce inhibition of sodium channels and cytotoxicity. Anesthesiology. 2016;124:1153.10.1097/ALN.0000000000001050

[16] [16] Zhou C, Huang JQ, Yang Q, Li T, Liu J, Qian ZY. Gold nanorods-based thermosensitive hydrogel produces selective long-lasting regional anesthesia triggered by photothermal activation of transient receptor potential vanilloid type-1 channels. Colloids Surf B. 2018;171:17.10.1016/j.colsurfb.2018.07.002

[17] [17] Kopach O, Zheng K, Dong L, Sapelkin A, Voitenko N, Sukhorukov GB, Rusakov DA. Nano-engineered microcapsules boost the treatment of persistent pain. Drug Deliv. 2018;25:435.10.1080/10717544.2018.1431981

[18] [18] Hu YW, Xu YT, Mintz RL, Luo X, Fang YQ, Lao YH, Chan HF, Li K, Lv SX, Chen GJ, Tao Y, Luo Y, Li MQ. Self-intensified synergy of a versatile biomimetic nanozyme and doxorubicin on electrospun fibers to inhibit postsurgical tumor recurrence and metastasis. Biomaterials. 2023;293: 121942.10.1016/j.biomaterials.2022.121942

[19] [19] Fang YQ, Luo X, Xu YT, Liu Z, Mintz RL, Yu HY, Yu X, Li K, Ju EG, Wang HX, Tang ZH, Tao Y, Li MQ. Sandwich-structured implants to obstruct multipath energy supply and trigger self-enhanced hypoxia-initiated chemotherapy against postsurgical tumor recurrence and metastasis. Adv Sci. 2023;10: e2300899.10.1002/advs.202300899

[20] [20] Lin ZJ, Liu BL, Wang HX, Zhan HL, Huang Y, Lu JX, Tao Y, Li MQ, Zhou XF. Nanoparticle-mediated intravesical delivery of conditioned medium derived from mesenchymal stem cells for interstitial cystitis/bladder pain syndrome treatment. Appl Mater Today. 2021;24: 101144.10.1016/j.apmt.2021.101144

[21] [21] Chen SF, Yao WF, Wang HX, Wang TN, Xiao X, Sun GL, Yang J, Guan Y, Zhang Z, Xia ZY, Li MQ, Tao Y, Hei ZQ. Injectable electrospun fiber-hydrogel composite sequentially releasing clonidine and ropivacaine for prolonged and walking regional analgesia. Theranostics. 2022;12:4904.10.7150/thno.74845

[22] [22] Wang L, Li T, Wang ZH, Hou JD, Liu ST, Yang Q, Yu L, Guo WH, Wang YJ, Guo BL, Huang WH, Wu YB. Injectable remote magnetic nanofiber/hydrogel multiscale scaffold for functional anisotropic skeletal muscle regeneration. Biomaterials. 2022;285: 121537.10.1016/j.biomaterials.2022.121537

[23] [23] Zhou XH, He XL, Shi K, Yuan LP, Yang Y, Liu QY, Ming Y, Yi C, Qian ZY. Injectable thermosensitive hydrogel containing erlotinib-loaded hollow mesoporous silica nanoparticles as a localized drug delivery system for NSCLC therapy. Adv Sci. 2020;7:2001442.10.1002/advs.202001442

[24] [24] Li M, Chen D, Sun X, Xu ZS, Yang YT, Song YM, Jiang F. An environmentally tolerant, highly stable, cellulose nanofiber-reinforced, conductive hydrogel multifunctional sensor. Carbohydr Polym. 2022;284: 119199.10.1016/j.carbpol.2022.119199

[25] [25] Jin YY, Zhang JB, Xu YT, Yi K, Li FF, Zhou HC, Wang HX, Chan HF, Lao YH, Lv SX, Tao Y, Li MQ. Stem cell-derived hepatocyte therapy using versatile biomimetic nanozyme incorporated nanofiber-reinforced decellularized extracellular matrix hydrogels for the treatment of acute liver failure. Bioact Mater. 2023;28:112–31.

[26] [26] He JX, Wu XL, Xie YF, Gao Y, McClements DJ, Zhang L, Zou LQ, Liu W. Capsaicin encapsulated in W/O/W double emulsions fabricated via ethanol-induced pectin gelling: improvement of bioaccessibility and reduction of irritation. Int J Biol Macromol. 2023;235: 123899.10.1016/j.ijbiomac.2023.123899

[27] [27] Zhang YJ, Yang J, Yin QQ, Yang LH, Liu J, Zhang WS. QX-OH, a QX-314 derivative agent, produces long-acting local anesthesia in rats. Eur J Pharm Sci. 2017;105:212.10.1016/j.ejps.2017.05.039

[28] [28] Wang Q, Zhang Y, Liu J, Zhang W. Quaternary lidocaine derivatives: past, present, and future. Drug Des Dev Ther. 2021;15:195.10.2147/DDDT.S291229

[29] [29] Gao Y, Cao EH, Julius D, Cheng YF. TRPV1 structures in nanodiscs reveal mechanisms of ligand and lipid action. Nature. 2016;534:347.10.1038/nature17964

[30] [30] García-Cáceres C, Balland E, Prevot V, Luquet S, Woods SC, Koch M, Horvath TL, Yi CX, Chowen JA, Verkhratsky A, Araque A, Bechmann I, Tschöp MH. Role of astrocytes, microglia, and tanycytes in brain control of systemic metabolism. Nat Neurosci. 2019;22:7.10.1038/s41593-018-0286-y

[31] [31] Li J, Wei YY, Zhou JL, Zou HL, Ma LL, Liu CX, Xiao Z, Liu XF, Tan XR, Yu T, Cao S. Activation of locus coeruleus-spinal cord noradrenergic neurons alleviates neuropathic pain in mice via reducing neuroinflammation from astrocytes and microglia in spinal dorsal horn. J Neuroinflammation. 2022;19:123.10.1186/s12974-022-02489-9

[32] [32] Yin SQ, Gao P, Yu LD, Zhu L, Yu WF, Chen Y, Yang LQ. Engineering 2D silicene-based mesoporous nanomedicine for in vivo near-infrared-triggered analgesia. Adv Sci. 2022;9: e2202735.10.1002/advs.202202735

[33] [33] Qiao B, Song XY, Zhang WY, Xu M, Zhuang BW, Li W, Guo HL, Wu WX, Huang GL, Zhang MR, Xie XY, Zhang N, Luan Y, Zhang CY. Intensity-adjustable pain management with prolonged duration based on phase-transitional nanoparticles-assisted ultrasound imaging-guided nerve blockade. J Nanobiotechnol. 2022;20:498.10.1186/s12951-022-01707-z

[34] [34] Ebbinghaus M, Müller S, Segond von Banchet G, Eitner A, Wank I, Hess A, Hilger I, Kamradt T, Schaible HG. Contribution of inflammation and bone destruction to pain in arthritis: a study in murine glucose-6-phosphate isomerase-induced arthritis. Arthritis Rheumatol. 2019;2016:71.

[35] [35] Sajid M, Khan MR, Ismail H, Latif S, Rahim AA, Mehboob R, Shah SA. Antidiabetic and antioxidant potential of Alnusnitida leaves in alloxan induced diabetic rats. J Ethnopharmacol. 2020;251: 112544.10.1016/j.jep.2020.112544

[36] [36] Zhang HR, Tao JL, Bai H, Yang EM, Zhong ZH, Liu XT, Gu YH, Lu SF. Changes in the serum metabolome of acute myocardial ischemia rat pretreatment with electroacupuncture. Am J Chin Med. 2019;47:1025.10.1142/S0192415X19500526