Self-Assembly as a Molecular Strategy to Improve Immunotherapy.
Self-Assembly as a Molecular Strategy to Improve Immunotherapy.
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DOI：
10.1021/acs.accounts.0c00438
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发表时间：
2020-11-17
影响因子：
18.3
通讯作者：
Jewell CM
中科院分区：
文献类型：
--
作者：
Froimchuk E;Carey ST;Edwards C;Jewell CM
免疫疗法利用个体的免疫系统来对抗癌症和自身免疫等疾病。在癌症期间，免疫系统通常无法检测和消灭癌细胞，而在自身免疫性疾病期间，免疫系统会错误地攻击自身组织。单克隆抗体和过继细胞疗法的最新进展证明了免疫疗法可以帮助在这些情况下指导更有效的反应。然而，尽管免疫疗法为患者带来了变革性的收益，但许多疗法并不是治愈性的，仅对一小部分患者有效，并且在区分健康细胞和患病细胞方面缺乏特异性，这可能会导致严重的副作用。从这个角度来看，自组装生物材料是有前途的技术，可以帮助解决免疫疗法面临的一些限制。例如，自组装可以精确控制免疫信号的组合和相对浓度，以及定向货物展示密度。这些功能支持选择性和效力，可以减少脱靶效应并实现模块化或个性化免疫疗法。驱动大多数系统在水溶液中自组装的潜在力是由疏水相互作用或电荷极性引起的。在本报告中，我们重点介绍了如何利用这些力量来自组装癌症和自身免疫性疾病的免疫疗法。疏水相互作用可以产生一系列复杂的结构，包括肽纳米纤维、纳米凝胶、胶束状颗粒以及与蛋白质载体的体内组装。某些具有疏水域的纳米纤维独特地受益于无需额外刺激信号即可引发免疫反应的能力。这一特性可以减少非特异性炎症，但也可能因其固有的刺激特性而限制纳米纤维的应用。胶束样颗粒已被开发出来，能够掺入一系列肿瘤特异性抗原，用于小鼠癌症模型的免疫治疗。关键观察结果表明，抗原的总剂量和每个颗粒的抗原展示密度都会影响免疫反应和免疫疗法的功效。这些进展是有希望的基准，可以揭示设计更特异性和个性化免疫疗法的设计原理。人们还开展了大量工作来开发利用静电相互作用来驱动带相反电荷的免疫信号组装的平台。这些策略受益于通过改变配制过程中阳离子与阴离子电荷的比率或电荷密度来调整组分之间的生物物理相互作用的能力。我们的实验室采用逐层组装方法，开发了完全由免疫信号组成的空心胶囊，用于癌症和自身免疫性疾病模型的治疗。该平台允许 100% 的免疫疗法由免疫信号组成，并完全预防多发性硬化症小鼠模型的疾病发作。逐层组装也被用来涂覆微针贴片，以将信号靶向真皮层中的免疫细胞。除了逐层组装之外，一步组装可以通过在溶液中混合阳离子和阴离子组分来实现。其他方法已经创建了利用氢键进行自组装的分子结构。工程自组装的创造力带来了可能有益于未来免疫疗法的关键见解，并揭示了需要进一步研究的方面。现在的挑战仍然是利用这些见解来推动新免疫疗法的开发进入临床环境。
Immunotherapies harness an individual’s immune system to battle diseases such as cancer and autoimmunity. During cancer the immune system often fails to detect and destroy cancerous cells, whereas during autoimmune disease, the immune system mistakenly attacks self-tissue. Immunotherapies can help guide more effective responses in these settings, as evidenced by recent advances with monoclonal antibodies and adoptive cell therapies. However, despite the transformative gains of immunotherapies for patients, many therapies are not curative, work only for a small subset of patients, and lack specificity in distinguishing between healthy and diseased cells, which can cause severe side effects. From this perspective, self-assembled biomaterials are promising technologies that could help address some of the limitations facing immunotherapies. For example, self-assembly allows precision control over the combination and relative concentration of immune cues, and directed cargo display densities. These capabilities support selectivity and potency that could decrease off-target effects and enable modular or personalized immunotherapies. The underlying forces driving self-assembly of most systems in aqueous solution result from hydrophobic interactions or charge polarity. In this Account, we highlight how these forces are being used to self-assemble immunotherapies for cancer and autoimmune disease. Hydrophobic interactions can create a range of intricate structures, including peptide nanofibers, nanogels, micelle-like particles, and in vivo assemblies with protein carriers. Certain nanofibers with hydrophobic domains uniquely benefit from the ability to elicit immune responses without additional stimulatory signals. This feature can reduce non-specific inflammation but may also limit the nanofiber’s application because of their inherent stimulatory properties. Micelle-like particles have been developed with the ability to incorporate a range of tumor-specific antigens for immunotherapies in mouse models of cancer. Key observations have revealed that both the total dose of antigen and display density of antigen per particle can impact immune response and efficacy of immunotherapies. These developments are promising benchmarks that could reveal design principles for engineering more specific and personalized immunotherapies. There has also been extensive work to develop platforms using electrostatic interactions to drive assembly of oppositely charged immune signals. These strategies benefit from the ability to tune biophysical interactions between components by altering the ratio of cationic to anionic charge during formulation, or the density of charge. Using a layer-by-layer assembly method, our lab developed hollow capsules composed entirely of immune signals for therapies in cancer and autoimmune disease models. This platform allowed for 100% of the immunotherapy to be composed of immune signals and completely prevents onset of disease in a mouse model of multiple sclerosis. Layer-by-layer assembly has also been used to coat microneedle patches to target signals to immune cells in the dermal layer. Alternative to layer-by-layer assembly, one step assembly can be achieved by mixing cationic and anionic components in solution. Additional approaches have created molecular structures that leverage hydrogen bonding for self-assembly. The creativity of engineered self-assembly has led to key insights that could benefit future immunotherapies and revealed aspects that require further study. The challenge now remains to utilize these insights to push development of new immunotherapeutics into clinical settings.
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影响因子：
9.7
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通讯作者：
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通讯作者：
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