多种新颖的免疫信号传导通路及相应调节药物的发现为通过调控免疫系统来治疗疾病带来了新的机遇，但是药物分子自身理化性质导致的不稳定性以及存在于组织、细胞、亚细胞层面的生理屏障严重妨碍了这些药物分子有效作用于靶点从而制约疗效。另一方面，非特异性的脱靶效应也会带来严重的毒副作用。本课题组将致力于在药物制剂和免疫治疗的交叉领域展开系列研究来克服上述挑战以便充分发挥免疫治疗的潜能。主要研究方向包括：（1）设计开发可克服药物不稳定性及有关生理屏障的制剂；（2）调节制剂在多尺度（如组织、细胞、亚细胞）的时空分布并研究其与免疫应答的相互关系；（3）探索制剂在不同疾病（如肿瘤、感染性疾病、自身免疫疾病）治疗中的应用并阐明其作用机制。

科学贡献

1. 开发了可高效实现肿瘤精准治疗的个体化疫苗制剂 肿瘤突变抗原（新抗原）的发现为肿瘤的精准治疗提供了可能性，但是如何安全有效“训练”免疫系统产生强大的新抗原特异性的T细胞应答是难点。我们把佐剂和新抗原偶联到高密度脂蛋白仿生纳米盘上制备成个体化肿瘤疫苗。经皮下注射后，纳米盘可显著提高新抗原和佐剂在淋巴结的回流，促进疫苗被树突状细胞内吞，增加并延长抗原在树突状细胞表面的提呈，从而有效激活新抗原特异性的T细胞并实现对多种不同肿瘤的精准治疗。

图1：个体化疫苗用于肿瘤的精准治疗

2. 开发了可有效用于肿瘤化学免疫疗法的化疗药物制剂 化疗药物除了可以直接杀灭肿瘤细胞外，还可通过引发肿瘤细胞的“免疫原性死亡”激活抗肿瘤T细胞应答，但是化疗药物存在半衰期短、肿瘤蓄积差等缺点，限制了其活性的发挥。我们把化疗药物通过磷脂锚定到高密度脂蛋白仿生纳米盘上制备纳米制剂。经静脉注射后，纳米盘可显著改善化疗药物的药代动力学和在肿瘤的分布，从而增加化疗药物直接杀灭肿瘤细胞的机会。被化疗药物杀灭的肿瘤细胞可提供肿瘤抗原并释放“危险信号”激活机体免疫系统产生抗肿瘤T细胞免疫应答，进一步促进残余肿瘤细胞的杀灭。

图2：化疗药物制剂用于肿瘤的化学免疫治疗

3. 开发了可提高亚单位抗原免疫原性的双佐剂制剂 以多肽和蛋白为代表的亚单位抗原因其制备和质控简单、安全性好等优点受到广泛关注，但是免疫原性弱极大限制了这类抗原的广泛应用。联用不同的免疫刺激剂是提高亚单位抗原免疫原性的重要手段，但是如何将不同类别的免疫刺激剂递送到靶点依然是一个难点。我们将两种不同的TLR激动剂通过疏水作用锚定到高密度脂蛋白仿生纳米盘上制备成了双佐剂制剂。该双佐剂制剂能有效将不同TLR激动剂递送到靶点，在与不同的亚单位抗原物理混合后可显著提高针对亚单位抗原的免疫应答。

图3：双佐剂制剂提高亚单位抗原的免疫原性

1. Levy O#, Kuai R#, Siren EM#, Bhere D, Milton Y, Nissar N, Biasia MD, Heinelt M, Reeve B, Abdi R, Alturki M, Fallatah M, Almalik A, Alhansan AH, Shah K, Karp JM. Shattering barriers towards clinically meaningful mesenchymal stromal cell (MSC) therapies. Science Advances, 2020; 6: eaba6884

2. Kuai R#, Singh PB#, Sun X#, Xu C, Najafabadi AH, Scheetz L, Yuan W, Xu Y, Hong H, Keskin DB, Wu CJ, Jain R, Schwendeman A, Moon JJ. Robust anti-tumor T cell response with efficient intratumoral infiltration by nanodisc cancer immunotherapy. Advanced Therapeutics, 2020, (In press)

3. Kadiyala P, Li D, Nunez F, Altshuler D, Doherty R, Kuai R, Yu M, Kamran N, Edwards M, Moon JJ, Lowenstein P, Castro M, Schwendeman A. High density lipoprotein-mimicking nanodiscs for chemo-immunotherapy against glioblastoma multiforme. ACS Nano, 2019, 13, 2, 1365-1384.

4. Kuai R#, Yuan W#, Son S, Nam J, Xu Y, Fan Y, Schwendeman A, Moon JJ. Elimination of established tumors with nanodisc-based combination chemoimmunotherapy. Science Advances, 2018; 4: eaao1736. Featured by ecancer, News Medical, ScienceNewsline, Newswise, Medical Press, EurekAlert.

5. Kuai R#, Sun X#, Yuan W, Xu Y, Schwendeman A, Moon JJ. Subcutaneous nanodisc vaccination with neo-antigens for combination cancer immunotherapy. Bioconjugate Chemistry, 2018, 29 (3), 771-775.

6. Nam J, Son S, Ochyl LJ, Kuai R, Schwendeman A and Moon JJ. Combination chemo-photothermal therapy elicits potent anti-tumor immunity and eliminates distal tumors. Nature Communications, 9, 1074 (2018).

7. Ochyl LJ, Bazzill JD, Park C, Xu Y, Kuai R, Moon JJ. PEGylated tumor cell membrane vesicles as a new vaccine platform for cancer immunotherapy. Biomaterials, 2018, 182, 157-166.

8. Park H#, Kuai R# , Jeon JE, Seo Y, Jung Y, Moon JJ, Schwendeman A, Cho S. Dual effective high-density lipoprotein-mimicking substance P nanodiscs for enhanced therapeutic angiogenesis in diabetic hindlimb ischemia. Biomaterials, 2018, 161, 69-80.

9. Kuai R, Sun X, Yuan W, Ochyl LJ, Xu Y, Najafabadi AH, Scheetz L, Yu M, Balwani I, Schwendeman A, Moon JJ. Dual TLR agonist nanodiscs as a strong adjuvant system for vaccines and immunotherapy. Journal of Controlled Release, 2018, 282, 131-139.

10. Kuai R#, Subramanian C#, White P#, Timmermann BN, Moon JJ, Cohen MS, Schwendeman A. Synthetic high density lipoprotein nanodiscs for targeted delivery to adrenocortical carcinoma. International Journal of Nanomedicine. 2017, 12, 6581-7594.

11. Kuai R, Ochyl LJ, Bahjat KS, Schwendeman A, Moon JJ. Designer vaccine nanodiscs for personalized cancer immunotherapy. Nature Materials, 2017, 16 (4), 489-496. Featured by Nature World News, Science Daily, Fierce Biotech, Yahoo! News, R&D, eCancer, Medical Physics Web, Nanotechweb, Technology Networks, Technology.org, C2W.nl, La Stampa, Scientias, Controlled Environments, Tech Times, STRF.ru, Business Standard, CanIndia, La Razon, Health Canal, E! Informador, My Science, Azonano, Nanowerk, Health Medicine, The Medical News, Health Medicinet.

12. Fan Y, Kuai R, Xu Y, Ochyl LJ, Irvine DJ, Moon JJ. Immunogenic cell death amplified by co-localized adjuvant delivery for cancer immunotherapy. Nano Letters, 2017, 17, 7387-7393.

13. Kuai R, Li D, Chen YE, Moon JJ, Schwendeman A. High-density lipoproteins: nature’s multifunctional nanoparticles. ACS Nano, 2016, 10 (3), 3015–3041.

14. Kuai R#, Yuan W#, Li W, Qin Y, Tang J, Yuan M, Fu L, Ran R, Zhang Z, He Q. Targeted delivery of cargoes into a murine solid tumor by a cell-penetrating peptide and cleavable poly(ethylene glycol) comodified liposomal delivery system via systemic administration. Molecular Pharmaceutics, 2011, 8 (6), 2151-2161.

15. Kuai R#, Yuan W#, Qin Y, Chen H, Tang J, Yuan M, Zhang Z, He Q. Efficient delivery of payload into tumor cells in a controlled manner by TAT and thiolytic cleavable PEG co-modified liposomes. Molecular Pharmaceutics, 2010, 7(5), 1816-1826.