近年來，癌症免疫治療越來越受歡迎，其中免疫檢查點阻斷透過激活人體自身的 T 細胞來靶向腫瘤，徹底改變了癌症治療。然而，儘管對於某些患者相當有效，但持續回應率仍然低得令人失望。這歸因於傳統抗體療法固有的一些生理障礙和限制。其中包括 T 細胞的多樣性、腫瘤內發現的免疫抑制微環境以及有效抑制細胞內檢查點易位過程的挑戰。
此外，全身性免疫毒性和對 T 細胞的不利影響使治療結果更加複雜。儘管細胞毒性 T 淋巴細胞的浸潤具有對抗轉移性腫瘤的潛力，但侵襲性腫瘤簇內的免疫特權和免疫原性反應不足等障礙阻礙了淋巴細胞的招募。因此，迫切需要創新策略來應對這些挑戰並提高免疫檢查點阻斷在癌症治療中的有效性。
在這邊，我們結合傳統化療及siRNA工程的基因療法，利用黑色素瘤肺轉移的作為癌症模型，報告了一種具有肺部標靶效果的免疫阻斷療法，與抗體療法不同的是我們利用紅血球當作車子遞送包有不同形狀核心的脂質奈米粒子且攜帶小分子藥物愛萊諾迪肯和PD-L1 siRNA到肺部，殺死細胞的同時將剩餘癌細胞的細胞膜與細胞質PD-L1 的表達沉默，消除T細胞被關機的步驟，進行T cell的癌症治療，同時也因為APC的噬紅血球作用，促進DC成熟並進一步刺激免疫反應。研究結果也表明，我們確實能夠有效地將PD-L1 siRNA遞送至肺部腫瘤區，讓T細胞浸潤腫瘤區，有效地抑制腫瘤的發展，克服傳統免疫檢查點抑制劑的盲點，延長小鼠的壽命，這種策略的開發有望開啟一條腫瘤免疫治療的新道路。

In recent years, cancer immunotherapy has garnered significant attention, with immune checkpoint blockade therapies transforming the landscape of cancer treatment by leveraging the body’s own T cells to target malignancies. While these therapies have shown efficacy in a subset of patients, overall response rates remain disappointingly low. This limited success is largely due to intrinsic physiological barriers and limitations associated with traditional antibody-based therapies, such as the heterogeneity of T cells, the immunosuppressive microenvironment within tumors, and challenges in effectively inhibiting intracellular checkpoint signaling pathways.
Additionally, systemic immune toxicity and adverse effects on T cells further complicate therapeutic outcomes. Although the infiltration of cytotoxic T lymphocytes (CTLs) presents a promising avenue for combating metastatic tumors, obstacles such as immune privilege within aggressive tumor clusters and inadequate immunogenic responses impede lymphocyte recruitment. Consequently, there is an urgent need for innovative strategies to overcome these challenges and improve the efficacy of immune checkpoint blockade in cancer treatment.
In this study, we present a novel lung-targeted immunotherapy using a melanoma lung metastasis model, which combines traditional chemotherapy with siRNA-engineered gene therapy. Our approach diverges from antibody-based therapies by utilizing erythrocytes as carriers to deliver differently shaped lipid nanoparticles loaded with the chemotherapeutic agent irinotecan and PD-L1 siRNA to the lungs. This dual strategy aims to eradicate cancer cells while silencing PD-L1 expression on the residual cancer cell membranes and cytoplasm, thereby preventing T cell deactivation and enhancing T cell-mediated anti-tumor activity. Furthermore, erythrophagocytosis by antigen-presenting cells (APCs) promotes dendritic cell (DC) maturation and amplifies the immune response.
Our experimental results indicate that this method successfully delivers PD-L1 siRNA to lung tumor sites, leading to substantial T cell infiltration into the tumors, effectively inhibiting tumor growth, and addressing the shortcomings of traditional immune checkpoint inhibitors. Additionally, this approach significantly extended the survival of treated mice. The development of this lung-targeted delivery system represents a promising advancement in tumor immunotherapy, potentially paving the way for more effective and targeted cancer treatments.

中文摘要 1
ABSTRACT 2
致謝 4
TABLE OF CONTENTS 5
LIST OF SCHEMES 8
LIST OF FIGURES 9
LIST OF TABLES 13
CHAPTER 1 INTRODUCTION 14
CHAPTER 2 LITERATURE REVIEW AND THEORY 18
2.1 OVERVIEW OF CANCER 18
2.1.1 Exploration of Lung Cancer 19
2.1.2 Understanding Melanoma Lung Metastasis 21
2.1.3 Nanotechnology in the Treatment of Lung Cancer 24
2.2 NANOPARTICLE-BASED DRUG DELIVERY 27
2.2.1 Lipid-based nanoparticle 30
2.2.2 Margination effect of blood flow 33
2.2.3 Surface modification and targeting to the lung 35
2.3 CELL-MEDIATED DRUGS DELIVERY SYSTEMS 39
2.3.1 RBC-based delivery systems 41
2.3.2 Red blood cell hitchhiking 44
2.3.3 RBC hitchhiking for lung targeting 46
2.4 NANO-IMMUNOTHERAPY FOR LUNG CANCER 49
2.4.1 Nucleic acid-based therapeutics 51
2.4.2 The Progress of Immunotherapy Targeting Checkpoint Inhibition in Lung Cancer 54
2.4.3 PD-L1 siRNA delivery systems in cancer cells 56
2.5 ERYTHROPHAGOCYTOSIS IS A FUNDAMENTAL STEP IN T CELL ACTIVATION. 60
2.5.1 Erythrophagocytosis by dendritic cells is significantly augmented during inflammation 61
CHAPTER 3 EXPERIMENTAL SECTION 62
3.1 MATERIALS 62
3.2 APPARATUS 66
3.3 METHOD 68
3.3.1 Synthesis of Prussian Blue Nanocube (PB) 68
3.3.2 Synthesis of hexagonal plate-shaped alpha iron oxide (α-IO) 69
3.3.3 Preparation of Cationic lipid nanoparticle (DLNP) and alpha iron oxide lipid nanoparticle (α-IO-DLNP) and Prussian blue lipid nanoparticle (PB-DLNP). 69
3.3.4 Blood collection and processing 71
3.3.5 Assembly of DLNPs to erythrocytes (DLNP@RBC) 71
3.3.6 Hitchhiking efficiency of DLNP on erythrocytes 72
3.3.7 Preparation of RBC SEM sample 72
3.3.8 The characterizations of particle 73
3.3.9 Cell culture 73
3.3.10 Cell viability assays 74
3.3.11 Cellular uptake analysis 75
3.3.12 Plasmid DNA (pDNA) transfection in vitro 76
3.3.13 Green/Red siRNA delivery by DLNP in vitro 78
3.3.14 PD-L1 siRNA-mediated protein knockdown in vitro 78
3.3.15 Lysotraker (endosomal escape) in virto 79
3.3.16 Biodistribution analysis by IVIS, flow cytometry, and tissue section in vivo 80
3.3.17 pDNA transfection and Red-siRNA delivery in vivo 83
3.3.18 Immunofluorescence staining of immune response in vivo 83
3.3.19 Flow cytometry analysis of immune response in vivo 84
CHAPTER 4 RESULTS AND DISCUSSION 85
4.1 CHARACTERIZATION OF NANOPARTICLES 85
4.1.1 Before and after surface modification of core nanoparticles with different geometries. 85
4.1.2 The efficient assembly of nanoparticles onto erythrocytes has been achieved 95
4.2 IN VITRO EXPERIMENT 101
4.2.1 After Coating Nanoparticles with Lipid, the Cell Viability of Each Group Becomes Quite Similar 101
4.2.2 Lipid Nanoparticle Effectively Taken Up by B16F10 Cells 102
4.2.3 DLNPs Can Successfully Escaped from Lysosome into Cytoplasm 106
4.2.4 DLNPs demonstrate proficient capability in co-delivering Cy3-siRNA 108
4.2.5 Effective downregulation of PD-L1 protein was accomplished via siRNA delivery in vitro. 111
4.2.6 DLNP@RBC Exhibits Excellent Interaction with B16F10 Cells 113
4.3 IN VIVO EXPERIMENT 115
4.3.1 DLNP@RBC at 125:1 Ratio Exhibited Excellent Lung Accumulation 115
4.3.2 α-IO-DLNP@RBC Demonstrate Superior in vivo Lung Targeting and Effectively Penetrated into Intratumoral site 117
4.3.3 In Vivo Co-Delivery into Tumour Tissue 119
4.3.4 The single treatment successfully reduced lung PD-L1 expression 120
4.3.5 Inhibits Lung Metastasis Progression in a late-stage B16F10 Metastasis Model 121
4.3.6 Therapeutic Strategies Enhance Intratumoral T Cell Infiltration 123
4.3.7 Erythrophagocytosis Triggers Lymphatic Immune Response 125
4.3.8 Processed RBCs boost DCs’ ability to consume RBCs 128
4.4 OUR STRATEGY IS ALSO HIGHLY EFFECTIVE FOR PDNA TRANSFECTION. 130
4.4.1 DLNPs Successfully Transfect Plasmid DNA Into Cells 130
4.4.2 α-IO-DLNP@RBC also demonstrates optimal plasmid DNA transfection in vivo. 132
4.5 SUPPLEMENTARY MATERIALS 134
CHAPTER 5 CONCLUSION 136
CHAPTER 6 REFERENCES 137

[1] R.L. Siegel, K.D. Miller, N.S. Wagle, A. Jemal, CA Cancer J Clin, 73 (2023) 17-48.
[2] K. Chaitanya Thandra, A. Barsouk, K. Saginala, J. Sukumar Aluru, A. Barsouk, Contemporary Oncology/Współczesna Onkologia, 25 (2021) 45-52.
[3] F. Perlikos, K.J. Harrington, K.N. Syrigos, Crit Rev Oncol Hematol, 87 (2013) 1-11.
[4] H. Sung, J. Ferlay, R.L. Siegel, M. Laversanne, I. Soerjomataram, A. Jemal, F. Bray, Ca-Cancer J Clin, 71 (2021) 209-249.
[5] T.B. Kratzer, P. Bandi, N.D. Freedman, R.A. Smith, W.D. Travis, A. Jemal, R.L. Siegel, Cancer, 130 (2024) 1330-1348.
[6] A.W. Lambert, D.R. Pattabiraman, R.A. Weinberg, Cell, 168 (2017) 670-691.
[7] H.B. Lengel, B. Mastrogiacomo, J.G. Connolly, K.S. Tan, Y. Liu, C.N. Fick, E.G. Dunne, D. He, M.B. Lankadasari, B.A. Satravada, Y.C. Sun, R. Kundra, C. Fong, S. Smith, G.J. Riely, C.M. Rudin, D.R. Gomez, D.B. Solit, M.F. Berger, B.T. Li, M.W. Mayo, I. Matei, D.C. Lyden, P.S. Adusumilli, N. Schultz, F. Sanchez-Vega, D.R. Jones, Cancer Cell, 41 (2023) 970-+.
[8] I.J. Fidler, Nat Rev Cancer, 3 (2003) 453-458.
[9] G.P. Gupta, J. Massagué, Cell, 127 (2006) 679-695.
[10] J.E. Talmadge, I.J. Fidler, Cancer Res, 70 (2010) 5649-5669.
[11] M. Gabelloni, L. Faggioni, R. Fusco, I. Simonetti, F. De Muzio, G. Giacobbe, A. Borgheresi, F. Bruno, D. Cozzi, F. Grassi, M. Scaglione, A. Giovagnoni, A. Barile, V. Miele, N. Gandolfo, V. Granata, J Pers Med, 13 (2023).
[12] A. Davoodvandi, M. Darvish, S. Borran, M. Nejati, S. Mazaheri, O.R. Tamtaji, M.R. Hamblin, N. Masoudian, H. Mirzaei, Int Immunopharmacol, 88 (2020).
[13] H. Regassa, A. Sourirajan, V. Kumar, S. Pandey, D. Kumar, K. Dev, Cancers, 14 (2022).
[14] A. Sharma, D. Shambhwani, S. Pandey, J. Singh, H. Lalhlenmawia, M. Kumarasamy, S.K. Singh, D.K. Chellappan, G. Gupta, P. Prasher, K. Dua, D. Kumar, Acs Omega, 8 (2023) 10-41.
[15] M. Fusciello, F. Fontana, S. Tähtinen, C. Capasso, S. Feola, B. Martins, J. Chiaro, K. Peltonen, L. Ylosmaki, E. Ylösmäki, F. Hamdan, O.K. Kari, J. Ndika, H. Alenius, A. Urtti, J.T. Hirvonen, H.A. Santos, V. Cerullo, Nat Commun, 10 (2019).
[16] S. Li, S. Xu, X. Liang, Y. Xue, J. Mei, Y. Ma, Y. Liu, Y. Liu, Adv Healthc Mater, 10 (2021) e2100078.
[17] Q.T. Jin, W.J. Zhu, J.F. Zhu, J.J. Zhu, J.J. Shen, Z. Liu, Y. Yang, Q. Chen, Adv Mater, 33 (2021).
[18] B. Pelaz, C.H. Alexiou, R.A. Alvarez -Puebla, F. Alves, A.M. Andrews, S. Ashraf, L.P. Balogh, L. Ballerini, A. Bestetti, C. Brendel, S. Bosi, M. Carril, W.C.W. Chan, C.Y. Chen, X.D. Chen, X.Y. Chen, Z. Cheng, D.X. Cui, J.Z. Du, C. Dullin, A. Escudero, N. Feliu, M.Y. Gao, M. George, Y. Gogotsi, A. Grünweller, Z.W. Gu, N.J. Halas, N. Hampp, R.K. Hartmann, M.C. Hersam, P. Hunziker, J. Jian, X.Y. Jiang, P. Jungebluth, P. Kadhiresan, K. Kataoka, A. Khademhosseini, J. Kopecek, N.A. Kotov, H.F. Krug, D.S. Lee, C.M. Lehr, K.W. Leong, X.J. Liang, M.L. Lim, L.M. Liz-Marzán, X.M. Ma, P. Macchiarini, H. Meng, H. Möhwald, P. Mulvaney, A.E. Nel, S.M. Nie, P. Nordlander, T. Okano, J. Oliveira, T.H. Park, R.M. Penner, M. Prato, V. Puntes, V.M. Rotello, A. Samarakoon, R.E. Schaak, Y.Q. Shen, S. Sjöqvist, A.G. Skirtach, M.G. Soliman, M.M. Stevens, H.W. Sung, B.Z. Tang, R. Tietze, B.N. Udugama, J.S. VanEpps, T. Weil, P.S. Weiss, I. Willner, Y.Z. Wu, L.L. Yang, Z. Yue, Q. Zhang, Q. Zhang, X.E. Zhang, Y.L. Zhao, X. Zhou, W.J. Parak, Acs Nano, 11 (2017) 2313-2381.
[19] N. Sanvicens, M.P. Marco, Trends Biotechnol, 26 (2008) 425-433.
[20] K. Dua, S.D. Shukla, T. de Jesus Andreoli Pinto, P.M. Hansbro, Interv Med Appl Sci, 9 (2017) 39-41.
[21] R. Singh, J.W. Lillard, Jr., Exp Mol Pathol, 86 (2009) 215-223.
[22] M. Elsabahy, G.S. Heo, S.M. Lim, G.R. Sun, K.L. Wooley, Chem Rev, 115 (2015) 10967-11011.
[23] E. Pérez-Herrero, A. Fernández-Medarde, Eur J Pharm Biopharm, 93 (2015) 52-79.
[24] J.C. Sung, B.L. Pulliam, D.A. Edwards, Trends Biotechnol, 25 (2007) 563-570.
[25] L. Xu, X. Wang, Y. Liu, G. Yang, R.J. Falconer, C.-X. Zhao, Advanced NanoBiomed Research, 2 (2022) 2100109.
[26] S. Fan, H. Han, Z. Yan, Y. Lu, B. He, Q. Zhang, Med Rev (2021), 3 (2023) 230-269.
[27] Y. Duan, A. Dhar, C. Patel, M. Khimani, S. Neogi, P. Sharma, N. Siva Kumar, R.L. Vekariya, RSC Adv, 10 (2020) 26777-26791.
[28] R. Tenchov, R. Bird, A.E. Curtze, Q. Zhou, Acs Nano, 15 (2021) 16982-17015.
[29] P. Decuzzi, R. Pasqualini, W. Arap, M. Ferrari, Pharm Res-Dord, 26 (2009) 235-243.
[30] R. Fahraeus, T. Lindqvist, Am J Physiol, 96 (1931) 562-568.
[31] H. Hadji, K. Bouchemal, J Control Release, 342 (2022) 93-110.
[32] F. Gentile, C. Chiappini, D. Fine, R.C. Bhavane, M.S. Peluccio, M.M. Cheng, X. Liu, M. Ferrari, P. Decuzzi, J Biomech, 41 (2008) 2312-2318.
[33] E. Blanco, H. Shen, M. Ferrari, Nat Biotechnol, 33 (2015) 941-951.
[34] N. Osman, N. Devnarain, C.A. Omolo, V. Fasiku, Y. Jaglal, T. Govender, Wiley Interdiscip Rev Nanomed Nanobiotechnol, 14 (2022) e1758.
[35] I. Ruseska, K. Fresacher, C. Petschacher, A. Zimmer, Nanomaterials (Basel), 11 (2021).
[36] S. Aryal, H. Park, J.F. Leary, J. Key, Int J Nanomedicine, 14 (2019) 6631-6644.
[37] Q. Cheng, T. Wei, L. Farbiak, L.T. Johnson, S.A. Dilliard, D.J. Siegwart, Nat Nanotechnol, 15 (2020) 313-320.
[38] T. Nakamura, Y. Sato, Y. Yamada, M.M. Abd Elwakil, S. Kimura, M.A. Younis, H. Harashima, Adv Drug Deliv Rev, 188 (2022) 114417.
[39] K. Swetha, N.G. Kotla, L. Tunki, A. Jayaraj, S.K. Bhargava, H. Hu, S.R. Bonam, R. Kurapati, Vaccines (Basel), 11 (2023).
[40] Q. Ma, J. Cao, Y. Gao, S. Han, Y. Liang, T. Zhang, X. Wang, Y. Sun, Nanoscale, 12 (2020) 15512-15527.
[41] Y. Du, S.J. Wang, M.L. Zhang, B.A. Chen, Y.F. Shen, Nanoscale Res Lett, 16 (2021).
[42] H. Yu, Z. Yang, F. Li, L. Xu, Y. Sun, Drug Deliv, 27 (2020) 1425-1437.
[43] L.X. Yang, Y. Yang, Y. Chen, Y.H. Xu, J.L. Peng, Adv Drug Deliver Rev, 187 (2022).
[44] E. Udofa, Z.M. Zhao, Adv Drug Deliver Rev, 204 (2024).
[45] Y.L. Wang, C.Y. Zhou, Y.N. Ding, M.Y. Liu, Z.J. Tai, Q. Jin, Y. Yang, Z.P. Li, M.Y. Yang, W. Gong, C.S. Gao, Int J Pharmaceut, 592 (2021).
[46] P.H.D. Nguyen, M.K. Jayasinghe, A.H. Le, B.Y. Peng, M.T.N. Le, Acs Nano, 17 (2023) 5187-5210.
[47] S. Tan, T. Wu, D. Zhang, Z. Zhang, Theranostics, 5 (2015) 863-881.
[48] Y.N. Dou, A. Kruse, P. Kotanko, H. Rosen, N.W. Levin, S. Thijssen, Kidney Int, 81 (2012) 1275-1276.
[49] C. Renoux, M. Faivre, A. Bessaa, L. Da Costa, P. Joly, A. Gauthier, P. Connes, Sci Rep-Uk, 9 (2019).
[50] M. Chen, Y. Leng, C. He, X. Li, L. Zhao, Y. Qu, Y. Wu, J Nanobiotechnology, 21 (2023) 288.
[51] Q. Xia, Y.T. Zhang, Z. Li, X.F. Hou, N.P. Feng, Acta Pharm Sin B, 9 (2019) 675-689.
[52] L. Rossi, F. Pierigè, A. Antonelli, N. Bigini, C. Gabucci, E. Peiretti, M. Magnani, Adv Drug Deliver Rev, 106 (2016) 73-87.
[53] W.Y. Zhang, M. Zhao, Y.L. Gao, X. Cheng, X.Y. Liu, S.K. Tang, Y.B. Peng, N. Wang, D.D. Hu, H.S. Peng, J.Q. Zhang, Q. Wang, Chem Eng J, 433 (2022).
[54] L. Koleva, E. Bovt, F. Ataullakhanov, E. Sinauridze, Pharmaceutics, 12 (2020).
[55] C.H. Villa, J. Seghatchian, V. Muzykantov, Transfus Apher Sci, 55 (2016) 275-280.
[56] P.M. Glassman, C.H. Villa, A. Ukidve, Z.M. Zhao, P. Smith, S. Mitragotri, A.J. Russell, J.S. Brenner, V.R. Muzykantov, Pharmaceutics, 12 (2020).
[57] I.V. Zelepukin, A.V. Yaremenko, V.O. Shipunova, A.V. Babenyshev, I.V. Balalaeva, P.I. Nikitin, S.M. Deyev, M.P. Nikitin, Nanoscale, 11 (2019) 1636-1646.
[58] J.S. Brenner, D.C. Pan, J.W. Myerson, O.A. Marcos-Contreras, C.H. Villa, P. Patel, H. Hekierski, S. Chatterjee, J.Q. Tao, H. Parhiz, K. Bhamidipati, T.G. Uhler, E.D. Hood, R.Y. Kiseleva, V.S. Shuvaev, T. Shuvaeva, M. Khoshnejad, I. Johnston, J.V. Gregory, J. Lahann, T. Wang, E. Cantu, W.M. Armstead, S. Mitragotri, V. Muzykantov, Nat Commun, 9 (2018) 2684.
[59] J.S. Brenner, S. Mitragotri, V.R. Muzykantov, Annu Rev Biomed Eng, 23 (2021) 225-248.
[60] G. Morgan, R. Ward, M. Barton, Clin Oncol-Uk, 16 (2004) 549-560.
[61] Z.M. Zhao, A. Ukidve, Y.S. Gao, J. Kim, S. Mitragotri, Sci Adv, 5 (2019).
[62] A.C. Anselmo, V. Gupta, B.J. Zern, D. Pan, M. Zakrewsky, V. Muzykantov, S. Mitragotri, Acs Nano, 7 (2013) 11129-11137.
[63] J.P. Zheng, C.H. Lu, Y.N. Ding, J.B. Zhang, F.Y. Tan, J.Z. Liu, G.B. Yang, Y.L. Wang, Z.P. Li, M.Y. Yang, Y. Yang, W. Gong, C.S. Gao, Int J Pharmaceut, 619 (2022).
[64] A. Lahiri, A. Maji, P.D. Potdar, N. Singh, P. Parikh, B. Bisht, A. Mukherjee, M.K. Paul, Mol Cancer, 22 (2023) 40.
[65] L.E. Raez, P.A. Cassileth, J.J. Schlesselman, K. Sridhar, S. Padmanabhan, E.Z. Fisher, P.A. Baldie, E.R. Podack, J Clin Oncol, 22 (2004) 2800-2807.
[66] E. Massarelli, V. Papadimitrakopoulou, J. Welsh, C. Tang, A.S. Tsao, Transl Lung Cancer Res, 3 (2014) 53-63.
[67] A. Zafar, M.J. Khan, J. Abu, A. Naeem, Mol Biol Rep, 51 (2024) 219.
[68] L. Osmani, F. Askin, E. Gabrielson, Q.K. Li, Semin Cancer Biol, 52 (2018) 103-109.
[69] J. Qu, Q. Mei, L. Chen, J. Zhou, Cancer Immunol Immunother, 70 (2021) 619-631.
[70] L. Chen, F. Chen, J. Li, Y. Pu, C. Yang, Y. Wang, Y. Lei, Y. Huang, Thorac Cancer, 13 (2022) 889-899.
[71] L.C. Villaruz, M.A. Socinski, Seminars in Thoracic and Cardiovascular Surgery, 23 (2011) 281-290.
[72] Z. Liu, M. Shi, Y. Ren, H. Xu, S. Weng, W. Ning, X. Ge, L. Liu, C. Guo, M. Duo, L. Li, J. Li, X. Han, Mol Cancer, 22 (2023) 35.
[73] Y. Lu, T. Zeng, H. Zhang, Y. Li, X. Zhu, H. Liu, B. Sun, C. Ji, T. Li, L. Huang, K. Peng, Z. Tang, L. Tang, Nano TransMed, 2 (2023) e9130018.
[74] X. Zhang, Z.-I. Lin, J. Yang, G.-L. Liu, Z. Hu, H. Huang, X. Li, Q. Liu, M. Ma, Z. Xu, G. Xu, K.-T. Yong, W.-C. Tsai, T.-H. Tsai, B.-T. Ko, C.-K. Chen, C. Yang, Nanomaterials2021.
[75] A. Gupta, J.L. Andresen, R.S. Manan, R. Langer, Adv Drug Deliv Rev, 178 (2021) 113834.
[76] T. Ramasamy, S. Munusamy, H.B. Ruttala, J.O. Kim, Biotechnol J, 16 (2021) e1900408.
[77] A. Wahane, A. Waghmode, A. Kapphahn, K. Dhuri, A. Gupta, R. Bahal, Molecules, 25 (2020).
[78] Y. Zhang, Q. Liu, X. Zhang, H. Huang, S. Tang, Y. Chai, Z. Xu, M. Li, X. Chen, J. Liu, C. Yang, J Nanobiotechnology, 20 (2022) 279.
[79] J. Chen, Y. Tang, Y. Liu, Y. Dou, AAPS PharmSciTech, 19 (2018) 3670-3680.
[80] J. DeVincenzo, R. Lambkin-Williams, T. Wilkinson, J. Cehelsky, S. Nochur, E. Walsh, R. Meyers, J. Gollob, A. Vaishnaw, Proc Natl Acad Sci U S A, 107 (2010) 8800-8805.
[81] C. Chakraborty, A.R. Sharma, G. Sharma, C.G.P. Doss, S.-S. Lee, Molecular Therapy - Nucleic Acids, 8 (2017) 132-143.
[82] S.J. Lee, M.J. Kim, I.C. Kwon, T.M. Roberts, Adv Drug Deliv Rev, 104 (2016) 2-15.
[83] S. Bagchi, R. Yuan, E.G. Engleman, Annu Rev Pathol, 16 (2021) 223-249.
[84] S.P. Kubli, T. Berger, D.V. Araujo, L.L. Siu, T.W. Mak, Nat Rev Drug Discov, 20 (2021) 899-919.
[85] Q. Lei, D. Wang, K. Sun, L. Wang, Y. Zhang, Front Cell Dev Biol, 8 (2020) 672.
[86] A. Passaro, J. Brahmer, S. Antonia, T. Mok, S. Peters, Journal of Clinical Oncology, 40 (2022) 598-+.
[87] J. Mazières, A. Drilon, A. Lusque, L. Mhanna, A.B. Cortot, L. Mezquita, A.A. Thai, C. Mascaux, S. Couraud, R. Veillon, M. Van Den Heuvel, J. Neal, N. Peled, M. Früh, T.L. Ng, V. Gounant, S. Popat, J. Diebold, J. Sabari, V.W. Zhu, S.I. Rothschild, P. Bironzo, A. Martinez-Marti, A. Curioni-Fontecedro, R. Rosell, M. Lattuca-Truc, M. Wiesweg, B. Besse, B. Solomon, F. Barlesi, R.D. Schouten, H. Wakelee, D.R. Camidge, G. Zalcman, S. Novello, S.I. Ou, J. Milia, O. Gautschi, Ann Oncol, 30 (2019) 1321-1328.
[88] R.S. Riley, C.H. June, R. Langer, M.J. Mitchell, Nature Reviews Drug Discovery, 18 (2019) 175-196.
[89] P.Y. Teo, C. Yang, L.M. Whilding, A.C. Parente-Pereira, J. Maher, A.J. George, J.L. Hedrick, Y.Y. Yang, S. Ghaem-Maghami, Adv Healthc Mater, 4 (2015) 1180-1189.
[90] A. Carrasco-Leon, A. Amundarain, N. Gomez-Echarte, F. Prosper, X. Agirre, Cancers (Basel), 13 (2021).
[91] S.H. El Moukhtari, E. Garbayo, A. Amundarain, S. Pascual-Gil, A. Carrasco-Leon, F. Prosper, X. Agirre, M.J. Blanco-Prieto, J Control Release, 361 (2023) 130-146.
[92] Y. Wu, W. Chen, Z.P. Xu, W. Gu, Front Immunol, 10 (2019) 2022.
[93] X. Han, L. Wang, T. Li, J. Zhang, D. Zhang, J. Li, Y. Xia, Y. Liu, W. Tan, Acs Nano, 14 (2020) 17524-17534.
[94] D. van Ens, C.M. Mousset, T.J.A. Hutten, A.B. van der Waart, D. Campillo-Davo, S. van der Heijden, D. Vodegel, H. Fredrix, R. Woestenenk, L. Parga-Vidal, J.H. Jansen, N.P.M. Schaap, E. Lion, H. Dolstra, W. Hobo, Bone Marrow Transplant, 55 (2020) 2308-2318.
[95] C. Li, X. Han, Pharm Res, 37 (2020) 109.
[96] X. Li, X. Zhou, J. Liu, J. Zhang, Y. Feng, F. Wang, Y. He, A. Wan, N. Filipczak, S.S.K. Yalamarty, Y. Jin, V.P. Torchilin, ACS Appl Mater Interfaces, 14 (2022) 28439-28454.
[97] A.L. Richards, J.E. Hendrickson, J.C. Zimring, K.E. Hudson, Transfusion, 56 (2016) 905-916.
[98] H. Ohyagi, N. Onai, T. Sato, S. Yotsumoto, J. Liu, H. Akiba, H. Yagita, K. Atarashi, K. Honda, A. Roers, W. Müller, K. Kurabayashi, M. Hosoi-Amaike, N. Takahashi, M. Hirokawa, K. Matsushima, K. Sawada, T. Ohteki, Immunity, 39 (2013) 584-598.
[99] D.Z. de Back, E.B. Kostova, M. van Kraaij, T.K. van den Berg, R. van Bruggen, Front Physiol, 5 (2014).
[100] J.E. Hendrickson, T.E. Chadwick, J.D. Roback, C.D. Hillyer, J.C. Zimring, Blood, 110 (2007) 2736-2743.
[101] K.K. Ki, H.M. Faddy, R.L. Flower, M.M. Dean, J Interf Cytok Res, 38 (2018) 111-121.
[102] B. Lelas Farhan, Zeena Usama, J., & Yusur Farhan, B., Revista Latinoamericana de Hipertension, 18(7) (2023).
[103] M. Hu, S. Furukawa, R. Ohtani, H. Sukegawa, Y. Nemoto, J. Reboul, S. Kitagawa, Y. Yamauchi, Angew Chem Int Edit, 51 (2012) 984-988.
[104] Y. Yang, X.L. Liu, Y.B. Lv, T.S. Herng, X.H. Xu, W.X. Xia, T.S. Zhang, J. Fang, W. Xiao, J. Ding, Adv Funct Mater, 25 (2015) 812-820.
[105] H.Z. Liang, Y.Q. Liu, A. Qileng, H.R. Shen, W.P. Liu, Z.L. Xu, Y.J. Liu, Biosens Bioelectron, 219 (2023).
[106] L.Y. Cao, Y.L. Liu, B.H. Zhang, L.H. Lu, Acs Appl Mater Inter, 2 (2010) 2339-2346.
[107] M. Wang, Y. Li, C.Q. Feng, G.Y. Zhao, Z.S. Wang, Chem-Asian J, 14 (2019) 1034-1041.
[108] M.Z. Zhu, H. Zhou, J.X. Shao, J.H. Feng, A.H. Yuan, J Alloy Compd, 749 (2018) 811-817.
[109] B.S. Wu, P. Wang, S.H. Teng, Colloid Surface A, 610 (2021).
[110] B. Liu, L.H. Tian, R. Wang, J.F. Yang, R. Guan, X.B. Chen, Appl Surf Sci, 422 (2017) 607-615.
[111] T.K. Jana, A. Pal, A.K. Mandal, S. Sarwar, P. Chakrabarti, K. Chatterjee, Chemistryselect, 2 (2017) 3068-3077.
[112] Y. Liu, L. Yu, Y. Hu, C. Guo, F. Zhang, X. Wen David Lou, Nanoscale, 4 (2012) 183-187.
[113] M. Mondal, D.K. Goswami, T.K. Bhattacharyya, J Electrochem Soc, 170 (2023).
[114] J. Wang, J.Z. Su, L.J. Guo, Chem-Asian J, 11 (2016) 2328-2334.
[115] P.G. Liu, D.L. Wu, Y. Gao, T. Wang, Y.Y. Tan, D.Z. Jia, J Alloy Compd, 738 (2018) 89-96.
[116] S.A. Smith, L.I. Selby, A.P.R. Johnston, G.K. Such, Bioconjug Chem, 30 (2019) 263-272.