Advances in rationally engineered cytokines for precision therapy in diabetic wound healing

Abstract

Diabetic wound healing presents a unique and complex challenge due to the impaired cellular and molecular functions associated with diabetes. Chronic wounds in diabetic patients are characterized by prolonged inflammation, reduced angiogenesis, and impaired collagen deposition, which significantly hinder the healing process. This comprehensive review focuses on the innovative applications of designer cytokines in precision therapy for diabetic wound healing, emphasizing the remarkable advancements made in overcoming the limitations of natural cytokines, such as their short half-life, potential cytotoxicity, and lack of specificity. We begin by detailing the intricate biological characteristics of diabetic wounds and the essential role that cytokines play in orchestrating the healing process. The review critically examines the constraints of natural cytokines and traces the evolution of synthetic alternatives, with a particular emphasis on peptide-based and nucleic acid-based artificial cytokines. Advanced strategies for designing these artificial cytokines are discussed, including molecular modifications, functional enhancements, and specificity improvements to better target pathological conditions in diabetic wounds. Furthermore, we explore the utilization of synthetic biology techniques to engineer effective cytokine-based therapies. The promising therapeutic potential of rationally designed cytokines is highlighted, showcasing their ability to modulate the wound microenvironment, enhance tissue regeneration, and reduce chronic inflammation. This review not only provides valuable perspectives on the future research directions but also offers insights into the potential clinical applications of these innovative therapies, aiming to significantly improve the outcomes for patients suffering from diabetic wounds.

Keywords

Cytokine engineering / diabetic wound healing / precision therapy / synthetic biology / rationally designed cytokines / molecular modifications

References

[1] Sorg H, Tilkorn DJ, Hager S, Hauser J, Mirastschijski U. Skin Wound Healing: An Update on the Current Knowledge and Concepts. Eur Surg Res. 2017; 58: 81-94.

[2] Rodrigues M, Kosaric N, Bonham CA, Gurtner GC. Wound Healing: A Cellular Perspective. Physiol Rev. 2019; 99: 665-706.

[3] Raziyeva K, Kim Y, Zharkinbekov Z, Kassymbek K, Jimi S, Saparov A. Immunology of Acute and Chronic Wound Healing. Biomolecules. 2021; 11: 700.

[4] Eming SA, Martin P, Tomic-Canic M. Wound repair and regeneration: mechanisms, signaling, and translation. Sci Transl Med. 2014; 6: 265sr6.

[5] Ahmad J. The diabetic foot. Diabetes Metab Syndr. 2016; 10: 48-60.

[6] Lim JZ, Ng NS, Thomas C. Prevention and treatment of diabetic foot ulcers. J R Soc Med. 2017; 110: 104-9.

[7] Armstrong DG, Swerdlow MA, Armstrong AA, Conte MS, Padula WV, Bus SA. Five year mortality and direct costs of care for people with diabetic foot complications are comparable to cancer. J Foot Ankle Res. 2020; 13: 16.

[8] Xu F, Zhang C, Graves DT. Abnormal cell responses and role of TNF-α in impaired diabetic wound healing. Biomed Res Int. 2013; 2013: 754802.

[9] Pakyari M, Farrokhi A, Maharlooei MK, Ghahary A. Critical Role of Transforming Growth Factor Beta in Different Phases of Wound Healing. Adv Wound Care (New Rochelle). 2013; 2: 215-24.

[10] Periayah MH, Halim AS, Mat Saad AZ. Mechanism Action of Platelets and Crucial Blood Coagulation Pathways in Hemostasis. Int J Hematol Oncol Stem Cell Res. 2017; 11: 319-27.

[11] Krzyszczyk P, Schloss R, Palmer A, Berthiaume F. The Role of Macrophages in Acute and Chronic Wound Healing and Interventions to Promote Pro-wound Healing Phenotypes. Front Physiol. 2018; 9: 419.

[12] Brem H, Tomic-Canic M. Cellular and molecular basis of wound healing in diabetes. J Clin Invest. 2007; 117: 1219-22.

[13] Yu H, Lin L, Zhang Z, Zhang H, Hu H. Targeting NF-κB pathway for the therapy of diseases: mechanism and clinical study. Signal Transduct Target Ther. 2020; 5: 209.

[14] Fuloria S, Subramaniyan V, Karupiah S, Kumari U, Sathasivam K, Meenakshi DU, et al. A Comprehensive Review on Source, Types, Effects, Nanotechnology, Detection, and Therapeutic Management of Reactive Carbonyl Species Associated with Various Chronic Diseases. Antioxidants (Basel). 2020; 9: 1075.

[15] Zhang JM, An J. Cytokines, inflammation, and pain. Int Anesthesiol Clin. 2007; 45: 27-37.

[16] Tanaka T, Narazaki M, Kishimoto T. IL-6 in inflammation, immunity, and disease. Cold Spring Harb Perspect Biol. 2014; 6: a016295.

[17] Nirenjen S, Narayanan J, Tamilanban T, Subramaniyan V, Chitra V, Fuloria NK, et al. Exploring the contribution of pro-inflammatory cytokines to impaired wound healing in diabetes. Front Immunol. 2023; 14: 1216321.

[18] Zenobia C, Hajishengallis G. Basic biology and role of interleukin-17 in immunity and inflammation. Periodontol 2000. 2015; 69: 142-59.

[19] Ge Y, Huang M, Yao YM. Biology of Interleukin-17 and Its Pathophysiological Significance in Sepsis. Front Immunol. 2020; 11: 1558.

[20] Hong WX, Hu MS, Esquivel M, Liang GY, Rennert RC, McArdle A, et al. The Role of Hypoxia-Inducible Factor in Wound Healing. Adv Wound Care (New Rochelle). 2014; 3: 390-9.

[21] Wang Z, Li W, Gou L, Zhou Y, Peng G, Zhang J, et al. Biodegradable and Antioxidant DNA Hydrogel as a Cytokine Delivery System for Diabetic Wound Healing. Adv Healthc Mater. 2022; 11: e2200782.

[22] Liu G, Zhou Y, Xu Z, Bao Z, Zheng L, Wu J. Janus hydrogel with dual antibacterial and angiogenesis functions for enhanced diabetic wound healing. Chin Chem Lett. 2023; 34: 107705.

[23] Xin P, Han S, Huang J, Zhou C, Zhang J, You X, et al. Natural okra-based hydrogel for chronic diabetic wound healing. Chin Chem Lett. 2023; 34: 108125.

[24] Zhang Z, Huang C, Guan S, Wang L, Yin H, Yin J, et al. Hybrid gelatin-ascorbyl phosphate scaffolds accelerate diabetic wound healing via ROS scavenging, angiogenesis and collagen remodeling. Biomater Adv. 2024; 158: 213779.

[25] Krasilnikova OA, Baranovskii DS, Lyundup AV, Shegay PV, Kaprin AD, Klabukov ID. Stem and Somatic Cell Monotherapy for the Treatment of Diabetic Foot Ulcers: Review of Clinical Studies and Mechanisms of Action. Stem Cell Rev Rep. 2022; 18: 1974-85.

[26] Lawrence WT, Diegelmann RF. Growth factors in wound healing. Clin Dermatol. 1994; 12: 157-69.

[27] Grant M, Jerdan J, Merimee TJ. Insulin-like growth factor-I modulates endothelial cell chemotaxis. J Clin Endocrinol Metab. 1987; 65: 370-1.

[28] Martinez FO, Gordon S. The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep. 2014; 6: 13.

[29] Sica A, Erreni M, Allavena P, Porta C. Macrophage polarization in pathology. Cell Mol Life Sci. 2015; 72: 4111-26.

[30] Tamilarasi GP, Sabarees G, Krishnan M, Gouthaman S, Alagarsamy V, Solomon VR. Electrospun Scaffold-based Antibiotic Therapeutics for Chronic Wound Recovery. Mini Rev Med Chem. 2023; 23: 1653-77.

[31] Staeva-Vieira TP, Freedman LP. 1,25-dihydroxyvitamin D₃ inhibits IFN-gamma and IL-4 levels during in vitro polarization of primary murine CD4⁺ T cells . J Immunol. 2002; 168: 1181-9.

[32] Du Cheyne C, Tay H, De Spiegelaere W. The complex TIE between macrophages and angiogenesis. Anat Histol Embryol. 2020; 49: 585-96.

[33] Demidova-Rice TN, Hamblin MR, Herman IM. Acute and impaired wound healing: pathophysiology and current methods for drug delivery, part 1: normal and chronic wounds: biology, causes, and approaches to care. Adv Skin Wound Care. 2012; 25: 304-14.

[34] Xue M, Jackson CJ. Extracellular Matrix Reorganization During Wound Healing and Its Impact on Abnormal Scarring. Adv Wound Care (New Rochelle). 2015; 4: 119-36.

[35] Li AW, Lim WA. Engineering cytokines and cytokine circuits. Science. 2020; 370: 1034-5.

[36] Grotendorst GR, Soma Y, Takehara K, Charette M. EGF and TGF-alpha are potent chemoattractants for endothelial cells and EGF-like peptides are present at sites of tissue regeneration. J Cell Physiol. 1989; 139: 617-23.

[37] Zheng X, Wu Y, Bi J, Huang Y, Cheng Y, Li Y, et al. The use of supercytokines, immunocytokines, engager cytokines, and other synthetic cytokines in immunotherapy. Cell Mol Immunol. 2022; 19: 192-209.

[38] Kim J, Yunn NO, Park M, Kim J, Park S, Kim Y, et al. Functional selectivity of insulin receptor revealed by aptamer-trapped receptor structures. Nat Commun. 2022; 13: 6500.

[39] Kammula US, White DE, Rosenberg SA. Trends in the safety of high dose bolus interleukin-2 administration in patients with metastatic cancer. Cancer. 1998; 83: 797-805.

[40] Sim GC, Radvanyi L. The IL-2 cytokine family in cancer immunotherapy. Cytokine Growth Factor Rev. 2014; 25: 377-90.

[41] Wang X, Rickert M, Garcia KC. Structure of the quaternary complex of interleukin-2 with its alpha, beta, and gammac receptors. Science. 2005; 310: 1159-63.

[42] Spolski R, Li P, Leonard WJ. Biology and regulation of IL-2: from molecular mechanisms to human therapy. Nat Rev Immunol. 2018; 18: 648-59.

[43] Levin AM, Bates DL, Ring AM, Krieg C, Lin JT, Su L, et al. Exploiting a natural conformational switch to engineer an interleukin-2 ‘superkine’. Nature. 2012; 484: 529-33.

[44] Mizui M. Natural and modified IL-2 for the treatment of cancer and autoimmune diseases. Clin Immunol. 2019; 206: 63-70.

[45] Junttila IS, Creusot RJ, Moraga I, Bates DL, Wong MT, Alonso MN, et al. Redirecting cell-type specific cytokine responses with engineered interleukin-4 superkines. Nat Chem Biol. 2012; 8: 990- 8.

[46] Glassman CR, Mathiharan YK, Jude KM, Su L, Panova O, Lupardus PJ, et al. Structural basis for IL-12 and IL-23 receptor sharing reveals a gateway for shaping actions on T versus NK cells. Cell. 2021; 184: 983-99.e24.

[47] Yin Y, Boesteanu AC, Binder ZA, Xu C, Reid RA, Rodriguez JL, et al. Checkpoint Blockade Reverses Anergy in IL-13Rα2 Humanized scFv-Based CAR T Cells to Treat Murine and Canine Gliomas. Mol Ther Oncolytics. 2018; 11: 20-38.

[48] Junttila IS. Tuning the Cytokine Responses: An Update on Interleukin (IL)-4 and IL-13 Receptor Complexes. Front Immunol. 2018; 9: 888.

[49] Zhu J, Li K, Xu L, Cai Y, Chen Y, Zhao X, et al. Discovery of novel selective PI3Kγ inhibitors through combining machine learning-based virtual screening with multiple protein structures and bio-evaluation. J Adv Res. 2021; 36: 1-13.

[50] Vazquez-Lombardi R, Loetsch C, Zinkl D, Jackson J, Schofield P, Deenick EK, et al. Potent antitumour activity of interleukin-2-Fc fusion proteins requires Fc-mediated depletion of regulatory T-cells. Nat Commun. 2017; 8: 15373.

[51] Charych DH, Hoch U, Langowski JL, Lee SR, Addepalli MK, Kirk PB, et al. NKTR-214, an Engineered Cytokine with Biased IL2 Receptor Binding, Increased Tumor Exposure, and Marked Efficacy in Mouse Tumor Models. Clin Cancer Res. 2016; 22: 680-90.

[52] To MD, Merchant F, Merchant N. MDNA11 is a long-acting IL-2 superkine that potentiates durable immune response in mouse tumor models and non-human primates. J Clin Oncol. 2021; 39: e14546.

[53] Zakrzewska M, Krowarsch D, Wiedlocha A, Olsnes S, Otlewski J. Highly stable mutants of human fibroblast growth factor-1 exhibit prolonged biological action. J Mol Biol. 2005; 352: 860-75.

[54] Szlachcic A, Zakrzewska M, Krowarsch D, Os V, Helland R, Smalås AO, et al. Structure of a highly stable mutant of human fibroblast growth factor 1. Acta Crystallogr D Biol Crystallogr. 2009; 65: 67-73.

[55] Schultz GS, Wysocki A. Interactions between extracellular matrix and growth factors in wound healing. Wound Repair Regen. 2009; 17: 153-62.

[56] Wedemeyer WJ, Welker E, Narayan M, Scheraga HA. Disulfide bonds and protein folding. Biochemistry. 2000; 39: 4207-16.

[57] Kobielak A, Zakrzewska M, Kostas M, Jakimowicz P, Otlewski J, Krowarsch D. Protease resistant variants of FGF1 with prolonged biological activity. Protein Pept Lett. 2014; 21: 434-43.

[58] Mahmood T, Shahbaz A, Hussain N, Ali R, Bashir H, Rizwan K. Recent advancements in fusion protein technologies in oncotherapy: A review. Int J Biol Macromol. 2023; 230: 123161.

[59] De Luca R, Neri D. Potentiation of PD-L1 blockade with a potency-matched dual cytokine-antibody fusion protein leads to cancer eradication in BALB/c-derived tumors but not in other mouse strains. Cancer Immunol Immunother. 2018; 67: 1381-91.

[60] Penafuerte C, Bautista-Lopez N, Boulassel MR, Routy JP, Galipeau J. The human ortholog of granulocyte macrophage colony-stimulating factor and interleukin-2 fusion protein induces potent ex vivo natural killer cell activation and maturation. Cancer Res. 2009; 69: 9020-8.

[61] Findeisen M, Allen TL, Henstridge DC, Kammoun H, Brandon AE, Baggio LL, et al. Treatment of type 2 diabetes with the designer cytokine IC7Fc. Nature. 2019; 574: 63-8.

[62] Hsu EJ, Cao X, Moon B, Bae J, Sun Z, Liu Z, et al. A cytokine receptor-masked IL2 prodrug selectively activates tumor-infiltrating lymphocytes for potent antitumor therapy. Nat Commun. 2021; 12: 2768.

[63] Mansurov A, Hosseinchi P, Chang K, Lauterbach AL, Gray LT, Alpar AT, et al. Masking the immunotoxicity of interleukin-12 by fusing it with a domain of its receptor via a tumour-protease-cleavable linker. Nat Biomed Eng. 2022; 6: 819-29.

[64] Zhao B, Wang Y, Tan X, Zheng X, Wang F, Ke K, et al. An Optogenetic Controllable T Cell System for Hepatocellular Carcinoma Immunotherapy. Theranostics. 2019; 9: 1837-50.

[65] Schwarz KA, Daringer NM, Dolberg TB, Leonard JN. Rewiring human cellular input-output using modular extracellular sensors. Nat Chem Biol. 2017; 13: 202-9.

[66] Chang ZL, Lorenzini MH, Chen X, Tran U, Bangayan NJ, Chen YY. Rewiring T-cell responses to soluble factors with chimeric antigen receptors. Nat Chem Biol. 2018; 14: 317-24.

[67] Scheller J, Engelowski E, Moll JM, Floss DM. Immunoreceptor Engineering and Synthetic Cytokine Signaling for Therapeutics. Trends Immunol. 2019; 40: 258-72.

[68] Yu M, Wu J, Shi J, Farokhzad OC. Nanotechnology for protein delivery: Overview and perspectives. J Control Release. 2016; 240: 24-37.

[69] Han S, Wu J. Development of a Lysine-Based Poly(ester amide) Library with High Biosafety and a Finely Tunable Structure for Spatiotemporal-Controlled Protein Delivery. ACS Appl Mater Interfaces. 2022; 14: 55944-56.

[70] Han S, Xin P, Guo Q, Cao Z, Huang H, Wu J. Oral Delivery of Protein Drugs via Lysine Polymer-Based Nanoparticle Platforms. Adv Healthc Mater. 2023; 12: e2300311.

[71] Wang Y, Zhang X, Wan K, Zhou N, Wei G, Su Z. Supramolecular peptide nano-assemblies for cancer diagnosis and therapy: from molecular design to material synthesis and function-specific applications. J Nanobiotechnology. 2021; 19: 253.

[72] Rodda AE, Meagher L, Nisbet DR, Forsythe JS. Specific control of cell-material interactions: Targeting cell receptors using ligand-functionalized polymer substrates. Prog Polym Sci. 2014; 39: 1312-47.

[73] Ye W, Yang Z, Cao F, Li H, Zhao T, Zhang H, et al. Articular cartilage reconstruction with TGF-β1-simulating self-assembling peptide hydrogel-based composite scaffold. Acta Biomater. 2022; 146: 94-106.

[74] D’Andrea LD, Iaccarino G, Fattorusso R, Sorriento D, Carannante C, Capasso D, et al. Targeting angiogenesis: structural characterization and biological properties of a de novo engineered VEGF mimicking peptide. Proc Natl Acad Sci U S A. 2005; 102: 14215-20.

[75] Rubert Pérez CM, Álvarez Z, Chen F, Aytun T, Stupp SI. Mimicking the Bioactivity of Fibroblast Growth Factor-2 Using Supramolecular Nanoribbons. ACS Biomater Sci Eng. 2017; 3: 2166-75.

[76] Shi W, Huang CJ, Xu XD, Jin GH, Huang RQ, Huang JF, et al. Transplantation of RADA16-BDNF peptide scaffold with human umbilical cord mesenchymal stem cells forced with CXCR4 and activated astrocytes for repair of traumatic brain injury. Acta Biomater. 2016; 45: 247-61.

[77] Colangelo AM, Bianco MR, Vitagliano L, Cavaliere C, Cirillo G, De Gioia L, et al. A new nerve growth factor-mimetic peptide active on neuropathic pain in rats. J Neurosci. 2008; 28: 2698-709.

[78] Mammadov R, Mammadov B, Toksoz S, Aydin B, Yagci R, Tekinay AB, et al. Heparin mimetic peptide nanofibers promote angiogenesis. Biomacromolecules. 2011; 12: 3508-19.

[79] Lee D, Rejinold NS, Jeong SD, Kim YC. Stimuli-Responsive Polypeptides for Biomedical Applications. Polymers (Basel). 2018; 10: 830.

[80] Lu H, Cheng J. Hexamethyldisilazane-mediated controlled polymerization of alpha-amino acid N-carboxyanhydrides . J Am Chem Soc. 2007; 129: 14114-5.

[81] Lu H, Cheng J. N-Trimethylsilyl amines for controlled ring-opening polymerization of amino acid N-carboxyanhydrides and facile end group functionalization of polypeptides . J Am Chem Soc. 2008; 130: 12562-3.

[82] Deming TJ. Synthesis of Side-Chain Modified Polypeptides. Chem Rev. 2016; 116: 786-808.

[83] Lee D, Noh I, Yoo J, Rejinold NS, Kim YC. pH-controllable cell-penetrating polypeptide that exhibits cancer targeting. Acta Biomater. 2017; 57: 187-96.

[84] Lee D, Lee SH, Na Y, Noh I, Ha J, Yoo J, et al. Conformation-switchable helical polypeptide eliciting selective pro-apoptotic activity for cancer therapy. J Control Release. 2017; 264: 24-33.

[85] Dong H, Wang M, Fan S, Wu C, Zhang C, Wu X, et al. Redox-Regulated Conformational Change of Disulfide-Rich Assembling Peptides. Angew Chem Int Ed Engl. 2022; 61: e202212829.

[86] Xu H, Yao Q, Cai C, Gou J, Zhang Y, Zhong H, et al. Amphiphilic poly(amino acid) based micelles applied to drug delivery: the in vitro and in vivo challenges and the corresponding potential strategies. J Control Release. 2015; 199: 84-97.

[87] Deng J, Gao N, Wang Y, Yi H, Fang S, Ma Y, et al. Self-assembled cationic micelles based on PEG-PLL-PLLeu hybrid polypeptides as highly effective gene vectors. Biomacromolecules. 2012; 13: 3795-804.

[88] Zhang J, Qiu Z, Fan J, He F, Kang W, Yang S, et al. Scan and Unlock: A Programmable DNA Molecular Automaton for Cell-Selective Activation of Ligand-Based Signaling. Angew Chem Int Ed Engl. 2021; 60: 6733-43.

[89] Wei L, Lin J, Cai C, Fang Z, Fu W. Drug-carrier/hydrogel scaffold for controlled growth of cells. Eur J Pharm Biopharm. 2011; 78: 346-54.

[90] Bae Y, Fukushima S, Harada A, Kataoka K. Design of environment-sensitive supramolecular assemblies for intracellular drug delivery: polymeric micelles that are responsive to intracellular pH change. Angew Chem Int Ed Engl. 2003; 42: 4640-3.

[91] Shirbin SJ, Ladewig K, Fu Q, Klimak M, Zhang X, Duan W, et al. Cisplatin-Induced Formation of Biocompatible and Biodegradable Polypeptide-Based Vesicles for Targeted Anticancer Drug Delivery. Biomacromolecules. 2015; 16: 2463-74.

[92] Mastria EM, Chen M, McDaniel JR, Li X, Hyun J, Dewhirst MW, et al. Doxorubicin-conjugated polypeptide nanoparticles inhibit metastasis in two murine models of carcinoma. J Control Release. 2015; 208: 52-8.

[93] Zhang DY, Seelig G. Dynamic DNA nanotechnology using strand-displacement reactions. Nat Chem. 2011; 3: 103-13.

[94] Seeman NC, Sleiman HF. DNA nanotechnology. Nat Rev Mater. 2017; 3: 17068.

[95] Ueki R, Atsuta S, Ueki A, Hoshiyama J, Li J, Hayashi Y, et al. DNA aptamer assemblies as fibroblast growth factor mimics and their application in stem cell culture. Chem Commun (Camb). 2019; 55: 2672-5.

[96] Ueki R, Uchida S, Kanda N, Yamada N, Ueki A, Akiyama M, et al. A chemically unmodified agonistic DNA with growth factor functionality for in vivo therapeutic application. Sci Adv. 2020; 6: eaay2801.

[97] Fan J, Wang HH, Xie S, Wang M, Nie Z. Engineering Cell-Surface Receptors with DNA Nanotechnology for Cell Manipulation. Chembiochem. 2020; 21: 282-93.

[98] Chen YJ, Groves B, Muscat RA, Seelig G. DNA nanotechnology from the test tube to the cell. Nat Nanotechnol. 2015; 10: 748-60.

[99] Ren X, Gelinas AD, von Carlowitz I, Janjic N, Pyle AM. Structural basis for IL-1α recognition by a modified DNA aptamer that specifically inhibits IL-1α signaling. Nat Commun. 2017; 8: 810.

[100] Li H, Wang M, Shi T, Yang S, Zhang J, Wang HH, et al. A DNA-Mediated Chemically Induced Dimerization (D-CID) Nanodevice for Nongenetic Receptor Engineering To Control Cell Behavior. Angew Chem Int Ed Engl. 2018; 57: 10226-30.

[101] Wang M, He F, Li H, Yang S, Zhang J, Ghosh P, et al. Near-Infrared Light-Activated DNA-Agonist Nanodevice for Nongenetically and Remotely Controlled Cellular Signaling and Behaviors in Live Animals. Nano Lett. 2019; 19: 2603-13.

[102] Li L, Yin J, Ma W, Tang L, Zou J, Yang L, et al. A DNA origami device spatially controls CD95 signalling to induce immune tolerance in rheumatoid arthritis. Nat Mater. 2024; 23: 993-1001.

[103] Yang S, Wang M, Tian D, Zhang X, Cui K, Lü S, et al. DNA-functionalized artificial mechanoreceptor for de novo force-responsive signaling. Nat Chem Biol. 2024; 20: 1066-77.

[104] Wu Y, Huang J, He H, Wang M, Yin G, Qi L, et al. Logic Nanodevice-Mediated Receptor Assembly for Nongenetic Regulation of Cell Behavior in Tumor-like Microenvironment. Nano Lett. 2023; 23: 1801-9.

[105] He F, Wang M, Wang J, Wang HH, Nie Z. An Extracellular miRNA-Responsive Artificial Receptor via Dynamic DNA Nano-assembly for Biomarker-Driven Therapy. Angew Chem Int Ed Engl. 2023; 62: e202305227.

[106] Lemmon MA, Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell. 2010; 141: 1117-34.

[107] Yunn NO, Lee J, Lee HS, Oh EJ, Park M, Park S, et al. An aptamer agonist of the insulin receptor acts as a positive or negative allosteric modulator, depending on its concentration. Exp Mol Med. 2022; 54: 531-41.

[108] Brideau-Andersen AD, Huang X, Sun SC, Chen TT, Stark D, Sas IJ, et al. Directed evolution of gene-shuffled IFN-alpha molecules with activity profiles tailored for treatment of chronic viral diseases. Proc Natl Acad Sci U S A. 2007; 104: 8269-74.

[109] Saxton RA, Tsutsumi N, Su LL, Abhiraman GC, Mohan K, Henneberg LT, et al. Structure-based decoupling of the pro- and anti-inflammatory functions of interleukin-10. Science. 2021; 371: eabc8433.