Fibroblast membrane-camouflaged nanoparticles for inflammation treatment in the early stage

Abstract

Unrestrained inflammation is harmful to tissue repair and regeneration. Immune cell membrane-camouflaged nanoparticles have been proven to show promise as inflammation targets and multitargeted inflammation controls in the treatment of severe inflammation. Prevention and early intervention of inflammation can reduce the risk of irreversible tissue damage and loss of function, but no cell membrane-camouflaged nanotechnology has been reported to achieve stage-specific treatment in these conditions. In this study, we investigated the prophylactic and therapeutic efficacy of fibroblast membrane-camouflaged nanoparticles for topical treatment of early inflammation (early pulpitis as the model) with the help of in-depth bioinformatics and molecular biology investigations in vitro and in vivo. Nanoparticles have been proven to act as sentinels to detect and competitively neutralize invasive Escherichia coli lipopolysaccharide (E. coli LPS) with resident fibroblasts to effectively inhibit the activation of intricate signaling pathways. Moreover, nanoparticles can alleviate the secretion of multiple inflammatory cytokines to achieve multitargeted anti-inflammatory effects, attenuating inflammatory conditions in the early stage. Our work verified the feasibility of fibroblast membrane-camouflaged nanoparticles for inflammation treatment in the early stage, which widens the potential cell types for inflammation regulation.

References

[1] Galler K, Weber M, Korkmaz Y, Widbiller M, Feuerer M. Inflammatory response mechanisms of the dentine-pulp complex and the periapical tissues. Int. J. Mol. Sci., 2021, 22: 1480.

[2] Grondman I, Pirvu A, Riza A, Ioana M, Netea M. Biomarkers of inflammation and the etiology of sepsis. Biochem. Soc., 2020, 48: 1-14.

[3] Grosheva I, . High-throughput screen identifies host and microbiota regulators of intestinal barrier function. Gastroenterology, 2020, 159: 1807-1823.

[4] Duncan H, Cooper P. Pulp innate immune defense: translational opportunities. J. Endod., 2020, 46: S10-S18.

[5] Sottero B, Rossin D, Poli G, Biasi F. Lipid oxidation products in the pathogenesis of inflammation-related gut diseases. Curr. Med. Chem., 2018, 25: 1311-1326.

[6] Gola A, . Commensal-driven immune zonation of the liver promotes host defence. Nature, 2021, 589: 131-136.

[7] Elsalhy M, Azizieh F, Raghupathy R. Cytokines as diagnostic markers of pulpal inflammation. Int. Endod. J., 2013, 46: 573-580.

[8] Risbud M, Shapiro I. Role of cytokines in intervertebral disc degeneration: pain and disc content. Nat. Rev. Rheumatol., 2014, 10: 44-56.

[9] Hamidzadeh K, Christensen S, Dalby E, Chandrasekaran P, Mosser D. Macrophages and the recovery from acute and chronic inflammation. Annu. Rev. Physiol., 2017, 79: 567-592.

[10] Nara K, . Anti-inflammatory roles of microRNA 21 in lipopolysaccharide-stimulated human dental pulp cells. J. Cell. Physiol., 2019, 234: 21331-21341.

[11] Smolen J, Aletaha D, Koeller M, Weisman M, Emery P. New therapies for treatment of rheumatoid arthritis. Lancet, 2007, 370: 1861-1874.

[12] Meng Q, . Capturing cytokines with advanced materials: a potential strategy to tackle COVID-19 cytokine storm. Adv. Mater., 2021, 33: e2100012.

[13] Yan H, . Engineering cell membrane-based nanotherapeutics to target inflammation. Adv. Sci., 2019, 6: 1900605.

[14] Jin K, Luo Z, Zhang B, Pang Z. Biomimetic nanoparticles for inflammation targeting. Acta Pharm. Sin. B, 2018, 8: 23-33.

[15] Gao C, . Treatment of atherosclerosis by macrophage-biomimetic nanoparticles via targeted pharmacotherapy and sequestration of proinflammatory cytokines. Nat. Commun., 2020, 11

[16] Fang R, Kroll A, Gao W, Zhang L. Cell membrane coating nanotechnology. Adv. Mater., 2018, 30: e1706759.

[17] Wei X, . T-cell-mimicking nanoparticles can neutralize HIV infectivity. Adv. Mater., 2018, 30: e1802233.

[18] Rao L, . Hybrid cellular membrane nanovesicles amplify macrophage immune responses against cancer recurrence and metastasis. Nat. Commun., 2020, 11

[19] Zhang Q, . Neutrophil membrane-coated nanoparticles inhibit synovial inflammation and alleviate joint damage in inflammatory arthritis. Nat. Nanotechnol., 2018, 13: 1182-1190.

[20] Ben-Akiva E, . Biomimetic anisotropic polymeric nanoparticles coated with red blood cell membranes for enhanced circulation and toxin removal. Sci. Adv., 2020, 6: eaay9035.

[21] Zhang L, . Light-activable on-demand release of nano-antibiotic platforms for precise synergy of thermochemotherapy on periodontitis. ACS Appl. Mater. Interfaces, 2020, 12: 3354-3362.

[22] Wang C, . Pretreated macrophage-membrane-coated gold nanocages for precise drug delivery for treatment of bacterial infections. Adv. Mater., 2018, 30: e1804023.

[23] Li S, . Biomimetic immunomodulation by crosstalk with nanoparticulate regulatory T cells. Matter, 2021, 4: 1-25,.

[24] Thamphiwatana S, . Macrophage-like nanoparticles concurrently absorbing endotoxins and proinflammatory cytokines for sepsis management. Proc. Natl Acad. Sci. USA, 2017, 114: 11488-11493.

[25] Kolb, P. et al. The importance of interventional timing in the bleomycin model of pulmonary fibrosis. Eur. Respir. J. 55, 1091105 (2020).

[26] Thaiss C, Zmora N, Levy M, Elinav E. The microbiome and innate immunity. Nature, 2016, 535: 65-74.

[27] Zhang A, . Mechanisms that lead to the regulation of NLRP3 inflammasome expression and activation in human dental pulp fibroblasts. Mol. Immunol., 2015, 66: 253-262.

[28] Sun G, Ren Q, Bai L, Zhang L. Phoenixin-20 suppresses lipopolysaccharide-induced inflammation in dental pulp cells. Chem. Biol. Interact., 2020, 318: 108971.

[29] Renard E, . Immune cells and molecular networks in experimentally induced pulpitis. J. Dent. Res., 2016, 95: 196-205.

[30] Chen Y, . Cell-membrane-cloaked oil nanosponges enable dual-modal detoxification. ACS Nano, 2019, 13: 7209-7215.

[31] Ricucci D, Loghin S, Siqueira J. Correlation between clinical and histologic pulp diagnoses. J. Endod., 2014, 40: 1932-1939.

[32] Zhan, Q. et al. Structural characterization and immunomodulatory activity of a novel acid polysaccharide isolated from the pulp of Rosa laevigata Michx fruit. Int. J. Biol. Macromol. 145, 1080–1090 (2020).

[33] Kim D, . Anti-inflammatory effects of glutamine on LPS-stimulated human dental pulp cells correlate with activation of MKP-1 and attenuation of the MAPK and NF-κB pathways. Int. Endod. J., 2015, 48: 220-228.

[34] Ryu J, . Reconstruction of LPS transfer cascade reveals structural determinants within LBP, CD14, and TLR4-MD2 for efficient LPS recognition and transfer. Immunity, 2017, 46: 38-50.

[35] Liu X, Cao Y, Zhang Y, Sun B, Liang H. Teneligliptin inhibits lipopolysaccharide-induced cytotoxicity and inflammation in dental pulp cells. Int. Immunopharmacol., 2019, 73: 57-63.

[36] He W, . LPS induces IL-8 expression through TLR4, MyD88, NF-kappaB and MAPK pathways in human dental pulp stem cells. Int. Endod. J., 2013, 46: 128-136.

[37] Gao X, . Nanoscale zeolitic imidazolate framework-8 activator of canonical MAPK signaling for bone repair. ACS Appl. Mater. Interfaces, 2021, 13: 97-111.

[38] Khorasani M, Hassanshahi G, Brodzikowska A, Khorramdelazad H. Role(s) of cytokines in pulpitis: latest evidence and therapeutic approaches. Cytokine, 2020, 126: 154896.

[39] Rechenberg D, Galicia J, Peters O. Biological markers for pulpal inflammation: a systematic review. PLoS ONE, 2016, 11: e0167289.

[40] Diakos C, Charles K, McMillan D, Clarke S. Cancer-related inflammation and treatment effectiveness. Lancet Oncol., 2014, 15: e493-e503.

[41] Zanini M, Meyer E, Simon S. Pulp inflammation diagnosis from clinical to inflammatory mediators: a systematic review. J. Endod., 2017, 43: 1033-1051.

[42] Giraud T, Jeanneau C, Bergmann M, Laurent P, About I. Tricalcium silicate capping materials modulate pulp healing and inflammatory activity in vitro. J. Endod., 2018, 44: 1686-1691.

[43] Anrather J, Iadecola C. Inflammation and stroke: an overview. Neurotherapeutics, 2016, 13: 661-670.

[44] Choy, E. Understanding the dynamics: pathways involved in the pathogenesis of rheumatoid arthritis. Rheumatology 51 (Suppl 5), v3–v11 (2012).

[45] Pasparakis M. Role of NF-κB in epithelial biology. Immunol. Rev., 2012, 246: 346-358.

[46] Jung J, . Simvastatin inhibits the expression of inflammatory cytokines and cell adhesion molecules induced by LPS in human dental pulp cells. Int. Endod. J., 2017, 50: 377-386.

[47] Feng Z, Li Q, Meng R, Yi B, Xu Q. METTL3 regulates alternative splicing of MyD88 upon the lipopolysaccharide-induced inflammatory response in human dental pulp cells. J. Cell. Mol. Med., 2018, 22: 2558-2568.

[48] Du M, . The LPS-inducible lncRNA Mirt2 is a negative regulator of inflammation. Nat. Commun., 2017, 8

[49] Wang D, . MicroRNA-223 negatively regulates LPS-induced inflammatory responses by targeting NLRP3 in human dental pulp fibroblasts. Int. Endod. J., 2021, 54: 241-254.

[50] Richardson A, . Vimentin is required for lung adenocarcinoma metastasis via heterotypic tumor cell-cancer-associated fibroblast interactions during collective invasion. Clin. Cancer Res., 2018, 24: 420-432.

[51] Liu Y, . TLR4 activation by lipopolysaccharide and Streptococcus mutans induces differential regulation of proliferation and migration in human dental pulp stem cells. J. Endod., 2014, 40: 1375-1381.

[52] Wang Y, . Macrophage membrane functionalized biomimetic nanoparticles for targeted anti-atherosclerosis applications. Theranostics, 2021, 11: 164-180.

[53] Ren X, . Red blood cell membrane camouflaged magnetic nanoclusters for imaging-guided photothermal therapy. Biomaterials, 2016, 92: 13-24.

[54] Wang Y, . Biomimetic nanotherapies: red blood cell based core-shell structured nanocomplexes for atherosclerosis management. Adv. Sci., 2019, 6: 1900172.

[55] Xia Q, Zhang Y, Li Z, Hou X, Feng N. Red blood cell membrane-camouflaged nanoparticles: a novel drug delivery system for antitumor application. Acta Pharm. Sin. B, 2019, 9: 675-689.

[56] Zhai Y, . Preparation and application of cell membrane-camouflaged nanoparticles for cancer therapy. Theranostics, 2017, 7: 2575-2592.

[57] Xie J, . Oriented assembly of cell-mimicking nanoparticles via a molecular affinity strategy for targeted drug delivery. ACS nano, 2019, 13: 5268-5277.

[58] Zhang Q, . Cellular nanosponges inhibit SARS-CoV-2 infectivity. Nano Lett., 2020, 20: 5570-5574.

[59] Wang C, . RNA-seq based transcriptome analysis of endothelial differentiation of bone marrow mesenchymal stem cells. Eur. J. Vasc. Endovasc. Surg., 2020, 59: 834-842.

[60] Bose R, . Bioengineered stem cell membrane functionalized nanocarriers for therapeutic targeting of severe hindlimb ischemia. Biomaterials, 2018, 185: 360-370.

[61] Zhao Y, . Wnt5a promotes inflammatory responses via nuclear factor κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways in human dental pulp cells. J. Biol. Chem., 2014, 289: 21028-21039.

[62] Shi X, Li Z, He Y, Jiang Q, Yang X. Effect of different dental burs for experimental induction of pulpitis in mice. Arch. Oral. Biol., 2017, 83: 252-257.

[63] Qiao W, . Lipopolysaccharide-induced DNA damage response activates nuclear factor κB signalling pathway via GATA4 in dental pulp cells. Int. Endod. J., 2019, 52: 1704-1715.

[64] Ning T, . Ageing affects the proliferation and mineralization of rat dental pulp stem cells under inflammatory conditions. Int. Endod. J., 2020, 53: 72-83.

Funding

National Natural Science Foundation of China (National Science Foundation of China)(No. 81991500, 81991501, 51903169, and 82170949)

China Postdoctoral Science Foundation(2019M663529)