Biomaterials-based nanoparticles conjugated to regulatory T cells provide a modular system for localized delivery of pharmacotherapeutic agents.
Biomaterials-based nanoparticles conjugated to regulatory T cells provide a modular system for localized delivery of pharmacotherapeutic agents.
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DOI：
10.1002/jbm.a.37442
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发表时间：
2023-03
影响因子：
4.9
通讯作者：
Brusko, Todd M.
中科院分区：
文献类型：
--
作者：
Marshall, Gregory P.;Cserny, Judit;Wang, Chun-Wei;Looney, Benjamin;Posgai, Amanda L.;Bacher, Rhonda;Keselowsky, Benjamin;Brusko, Todd M.
1型糖尿病(T1D)面临两个治疗挑战：纠正潜在的自身免疫和恢复β细胞团的需要。我们利用调节性T细胞(Tregs)和T细胞受体(Tcr)的独特能力来指导耐受诱导以及组织局部治疗药物的输送，以恢复内源性β细胞功能。具体地说，我们设计了一种组合疗法，将基于生物材料的聚(乳酸-乙醇酸)纳米颗粒与共负载的Treg生长因子、IL-2和β细胞再生剂骆驼蓬碱(一种酪氨酸调节的激酶1A[DYRK1a]抑制剂)连接到Treg表面。我们观察到在体外至少7 天内，IL-2和骆驼蓬碱从纳米粒中持续洗脱。当IL-2纳米颗粒与原代人类Tregs结合时，提供了足够的IL-2受体信号来支持STAT5的磷酸化，以维持培养中的表型稳定性和生存能力。在纳米颗粒-细胞偶联过程中加入多聚L赖氨酸显著提高了偶联效率，提供了足够的IL-2来支持IL-2依赖的CTLL-2细胞和原代小鼠Tregs的体外增殖。在12周大的雌性非肥胖型糖尿病小鼠中，过继转移IL-2/骆驼蓬碱纳米颗粒结合的NOD.BDC2.5 Tregs，表达胰岛抗原特异性TCR，显著预防了糖尿病在体内保存的生存能力。这些数据为开发生物材料优化的细胞疗法提供了临床前基础，以恢复免疫耐受，并通过胰岛内受体靶向药物传递促进β-细胞在T1D的增殖。
Type 1 diabetes (T1D) presents with two therapeutic challenges: the need to correct underlying autoimmunity and restore β‐cell mass. We harnessed the unique capacity of regulatory T cells (Tregs) and the T cell receptor (TCR) to direct tolerance induction along with tissue‐localized delivery of therapeutic agents to restore endogenous β‐cell function. Specifically, we designed a combinatorial therapy involving biomaterials‐based poly(lactic‐co‐glycolic acid) nanoparticles co‐loaded with the Treg growth factor, IL‐2, and the β‐cell regenerative agent, harmine (a tyrosine‐regulated kinase 1A [DYRK1A] inhibitor), conjugated to the surface of Tregs. We observed continuous elution of IL‐2 and harmine from nanoparticles for at least 7 days in vitro. When conjugated to primary human Tregs, IL‐2 nanoparticles provided sufficient IL‐2 receptor signaling to support STAT5 phosphorylation for sustained phenotypic stability and viability in culture. Inclusion of poly‐L‐lysine (PLL) during nanoparticle‐cell coupling dramatically increased conjugation efficiency, providing sufficient IL‐2 to support in vitro proliferation of IL‐2‐dependent CTLL‐2 cells and primary murine Tregs. In 12‐week‐old female non‐obese diabetic mice, adoptive transfer of IL‐2/harmine nanoparticle‐conjugated NOD.BDC2.5 Tregs, which express an islet antigen‐specific TCR, significantly prevented diabetes demonstrating preserved in vivo viability. These data provide the preclinical basis to develop a biomaterials‐optimized cellular therapy to restore immune tolerance and promote β‐cell proliferation in T1D through receptor‐targeted drug delivery within pancreatic islets.
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影响因子：
16.2
作者：
Chiang JL;Maahs DM;Garvey KC;Hood KK;Laffel LM;Weinzimer SA;Wolfsdorf JI;Schatz D
通讯作者：
Schatz D
影响因子：
2.6
作者：
Brusko, Todd;Atkinson, Mark
通讯作者：
Atkinson, Mark
影响因子：
4.4
作者：
Jamison, Braxton L.;Neef, Tobias;Haskins, Kathryn
通讯作者：
Haskins, Kathryn
DOI：
10.1016/j.clim.2015.03.023
发表时间：
2015-09
期刊：
Clinical immunology (Orlando, Fla.)
影响因子：
--
作者：
Lewis JS;Dolgova NV;Zhang Y;Xia CQ;Wasserfall CH;Atkinson MA;Clare-Salzler MJ;Keselowsky BG
通讯作者：
Keselowsky BG
影响因子：
7.3
作者：
Brusko MA;Stewart JM;Posgai AL;Wasserfall CH;Atkinson MA;Brusko TM;Keselowsky BG
通讯作者：
Keselowsky BG