Synthetic Biology-Based Engineering Cells for Drug Delivery

Abstract

Although drug delivery technology has promoted the clinical translation of small molecule drugs, there is an urgent need for advanced delivery systems to overcome complex physiological barriers and the increasing development of biological drugs. This review overviews the emerging applications of synthetic biology-based engineered cells for drug delivery. We first introduce synthetic biology strategies to engineer cells for biological drug delivery and discuss the benefits in terms of specificity, intelligence, and controllability. Furthermore, we highlight the cutting-edge advancements at the convergence of synthetic biology and nanotechnology in drug delivery. Nanotechnology expands the engineering design and construction concepts of synthetic biology, and synthetic biology drives the development for biotechnology-driven nanomaterial synthesis. In the future, synthetic biology-based engineered cells may be developed to be more modular, standardized, and intelligent, leading to significant breakthroughs in the construction of advanced drug delivery systems.

Keywords

drug delivery / engineered cells / synthetic biology

References

[1] R. Langer, “Drug Delivery and Targeting,” Nature 392 (1998): 5-10.

[2] T. M. Allen and P. R. Cullis, “Drug Delivery Systems: Entering the Mainstream,” Science 303 (2004): 1818-1822.

[3] M. J. Mitchell, M. M. Billingsley, R. M. Haley, M. E. Wechsler, N. A. Peppas, and R. Langer, “Engineering Precision Nanoparticles for Drug Delivery,” Nature Reviews Drug Discovery 20 (2021): 101-124.

[4] J. D. Martin, H. Cabral, T. Stylianopoulos, and R. K. Jain, “Improving Cancer Immunotherapy Using Nanomedicines: Progress, Opportunities and Challenges,” Nature Reviews Clinical Oncology 17 (2020): 251-266.

[5] F. Farjadian, A. Ghasemi, O. Gohari, A. Roointan, M. Karimi, and M. R. Hamblin, “Nanopharmaceuticals and Nanomedicines Currently on the Market: Challenges and Opportunities,” Nanomedicine 14 (2019): 93-126.

[6] D. E. Cameron, C. J. Bashor, and J. J. Collins, “A Brief History of Synthetic Biology,” Nature Reviews Microbiology 12 (2014): 381-390.

[7] F. Meng and T. Ellis, “The Second Decade of Synthetic Biology: 2010-2020,” Nature Communications 11 (2020): 5174.

[8] M. P. McNerney, K. E. Doiron, T. L. Ng, T. Z. Chang, and P. A. Silver, “Theranostic Cells: Emerging Clinical Applications of Synthetic Biology,” Nature Reviews Genetics 22 (2021): 730-746.

[9] A. Cubillos-Ruiz, T. Guo, A. Sokolovska, et al., “Engineering Living Therapeutics With Synthetic Biology,” Nature Reviews Drug Discovery 20 (2021): 941-960.

[10] N. Zhao, Y. Song, X. Xie, et al., “Synthetic Biology-Inspired Cell Engineering in Diagnosis, Treatment and Drug Development,” Signal Transduction and Targeted Therapy 8 (2023): 112.

[11] C. J. Bashor, I. B. Hilton, H. Bandukwala, D. M. Smith, and O. Veiseh, “Engineering the Next Generation of Cell-Based Therapeutics,” Nature Reviews Drug Discovery 21 (2022): 655-675.

[12] P. Braendstrup, B. L. Levine, and M. Ruella, “The Long Road to the First FDA-Approved Gene Therapy: Chimeric Antigen Receptor T Cells Targeting CD19,” Cytotherapy 22 (2020): 57-69.

[13] W. Li, Z. Su, M. Hao, C. Ju, and C. Zhang, “Cytopharmaceuticals: An Emerging Paradigm for Drug Delivery,” Journal of Controlled Release 328 (2020): 313-324.

[14] S. Ausländer, D. Ausländer, and M. Fussenegger, “Synthetic Biology—The Synthesis of Biology,” Angewandte Chemie International Edition 56 (2017): 6396-6419.

[15] S. Hirschi, T. R. Ward, W. P. Meier, D. J. Müller, and D. Fotiadis, “Synthetic Biology: Bottom-Up Assembly of Molecular Systems,” Chemical Reviews 122 (2022): 16294-16328.

[16] S. Rémy, L. Tesson, S. Ménoret, C. Usal, A. M. Scharenberg, and I. Anegon, “Zinc-Finger Nucleases: A Powerful Tool for Genetic Engineering of Animals,” Transgenic Research 19 (2010): 363-371.

[17] J. K. Joung and J. D. Sander, “TALENs: A Widely Applicable Technology for Targeted Genome Editing,” Nature Reviews Molecular Cell Biology 14 (2013): 49-55.

[18] R. C. Sterner and R. M. Sterner, “CAR-T Cell Therapy: Current Limitations and Potential Strategies,” Blood Cancer Journal 11 (2021): 69.

[19] F. Sinclair, A. A. Begum, C. C. Dai, I. Toth, and P. M. Moyle, “Recent Advances in the Delivery and Applications of Nonviral CRISPR/Cas9 Gene Editing,” Drug Delivery and Translational Research 13 (2023): 1500-1519.

[20] A. Pickar-Oliver and C. A. Gersbach, “The Next Generation of CRISPR-Cas Technologies and Applications,” Nature Reviews Molecular Cell Biology 20 (2019): 490-507.

[21] A. Katti, B. J. Diaz, C. M. Caragine, N. E. Sanjana, and L. E. Dow, “CRISPR in Cancer Biology and Therapy,” Nature Reviews Cancer 22 (2022): 259-279.

[22] Y. R. Choi, K. H. Collins, L. E. Springer, et al., “A Genome-Engineered Bioartificial Implant for Autoregulated Anticytokine Drug Delivery,” Science Advances 7 (2021): eabj1414.

[23] Y. Lu, J. Xue, T. Deng, et al., “Safety and Feasibility of CRISPR-Edited T Cells in Patients with Refractory Non-Small-Cell Lung Cancer,” Nature Medicine 26 (2020): 732-740.

[24] M. J. Volk, V. G. Tran, S. I. Tan, et al., “Metabolic Engineering: Methodologies and Applications,” Chemical Reviews 123 (2023): 5521-5570.

[25] R. Geiger, J. C. Rieckmann, T. Wolf, et al., “L-Arginine Modulates T Cell Metabolism and Enhances Survival and Anti-Tumor Activity,” Cell 167 (2016): 829-842.

[26] V. Bronte and P. Zanovello, “Regulation of Immune Responses by L-Arginine Metabolism,” Nature Reviews Immunology 5 (2005): 641-654.

[27] X. He, H. Lin, L. Yuan, and B. Li, “Combination Therapy with L-Arginine and α-PD-L1 Antibody Boosts Immune Response against Osteosarcoma in Immunocompetent Mice,” Cancer Biology & Therapy 18 (2017): 94-100.

[28] F. P. Canale, C. Basso, G. Antonini, et al., “Metabolic Modulation of Tumours With Engineered Bacteria for Immunotherapy,” Nature 598 (2021): 662-666.

[29] S. Jiang, R. Wang, D. Wang, et al., “Metabolic Reprogramming and Biosensor-Assisted Mutagenesis Screening for High-Level Production of L-Arginine in Escherichia Coli,” Metabolic Engineering 76 (2023): 146-157.

[30] N. Knödlseder, M. J. Fábrega, J. Santos-Moreno, et al., “Delivery of a Sebum Modulator by an Engineered Skin Microbe in Mice,” Nature Biotechnology 42: 1661-1666.

[31] Y. H. Chan and S. G. Boxer, “Model Membrane Systems and Their Applications,” Current Opinion in Chemical Biology 11 (2007): 581-587.

[32] N. J. Gaut and K. P. Adamala, “Reconstituting Natural Cell Elements in Synthetic Cells,” Advanced Biology 5 (2021): e2000188.

[33] Q. Wang, Z. Hu, Z. Li, T. Liu, and G. Bian, “Exploring the Application and Prospects of Synthetic Biology in Engineered Living Materials,” Advanced Materials: e2305828.

[34] A. V. Pinheiro, D. Han, W. M. Shih, and H. Yan, “Challenges and Opportunities for Structural DNA Nanotechnology,” Nature Nanotechnology 6 (2011): 763-772.

[35] S. Dey, C. Fan, K. V. Gothelf, et al., “DNA Origami,” Nature Reviews Methods Primers 1 (2021): 13.

[36] R. Veneziano, T. J. Moyer, M. B. Stone, et al., “Role of Nanoscale Antigen Organization on B-cell Activation Probed Using DNA Origami,” Nature Nanotechnology 15 (2020): 716-723.

[37] X. Wu, C. Yang, H. Wang, et al., “Genetically Encoded DNA Origami for Gene Therapy in Vivo,” Journal of the American Chemical Society 145 (2023): 9343-9353.

[38] C. Gu, T. Zhang, C. Lv, Y. Liu, Y. Wang, and G. Zhao, “His-Mediated Reversible Self-Assembly of Ferritin Nanocages through Two Different Switches for Encapsulation of Cargo Molecules,” ACS Nano 14 (2020): 17080-17090.

[39] B. Nguyen and N. H. Tolia, “Protein-Based Antigen Presentation Platforms for Nanoparticle Vaccines,” Npj Vaccines 6 (2021): 70.

[40] W. Jiang, Z. Wu, Z. Gao, et al., “Artificial Cells: Past, Present and Future,” ACS Nano 16 (2022): 15705-15733.

[41] D. G. Gibson, J. I. Glass, C. Lartigue, et al., “Creation of a Bacterial Cell Controlled by a Chemically Synthesized Genome,” Science 329 (2010): 52-56.

[42] C. A. Hutchison 3rd, R. Y. Chuang, V. N. Noskov, N. Assad-Garcia, et al., “Design and Synthesis of a Minimal Bacterial Genome,” Science 351 (2016): aad6253.

[43] J. F. Pelletier, L. Sun, K. S. Wise, et al., “Genetic Requirements for Cell Division in a Genomically Minimal Cell,” Cell 184 (2021): 2430-2440.

[44] P. van Nies, I. Westerlaken, D. Blanken, M. Salas, M. Mencía, and C. Danelon, “Self-Replication of DNA by Its Encoded Proteins in Liposome-Based Synthetic Cells,” Nature Communications 9 (2018): 1583.

[45] Z. Chen, J. Wang, W. Sun, et al., “Synthetic Beta Cells for Fusion-Mediated Dynamic Insulin Secretion,” Nature Chemical Biology 14 (2018): 86-93.

[46] Q. Lv, L. Cheng, Y. Lu, X. Zhang, et al., “Thermosensitive Exosome-Liposome Hybrid Nanoparticle-Mediated Chemoimmunotherapy for Improved Treatment of Metastatic Peritoneal Cancer,” Advanced Science 7 (2020): 2000515.

[47] A. C. Anselmo, Y. Gokarn, and S. Mitragotri, “Non-Invasive Delivery Strategies for Biologics,” Nature Reviews Drug Discovery 18 (2019): 19-40.

[48] G. C. Terstappen, A. H. Meyer, R. D. Bell, and W. Zhang, “Strategies for Delivering Therapeutics across the Blood-Brain Barrier,” Nature Reviews Drug Discovery 20 (2021): 362-383.

[49] A. M. Vargason, A. C. Anselmo, and S. Mitragotri, “The Evolution of Commercial Drug Delivery Technologies,” Nature Biomedical Engineering 5 (2021): 951-967.

[50] X. Zhang, J. Wang, Z. Chen, et al., “Engineering PD-1-Presenting Platelets for Cancer Immunotherapy,” Nano Letters 18 (2018): 5716-5725.

[51] X. Zhang, Y. Kang, J. Wang, et al., “Engineered PD-L1-Expressing Platelets Reverse New-Onset Type 1 Diabetes,” Advanced Materials 32 (2020): e1907692.

[52] C. R. Gurbatri, I. Lia, R. Vincent, et al., “Engineered Probiotics for Local Tumor Delivery of Checkpoint Blockade Nanobodies,” Science Translational Medicine 12 (2020): e1907692.

[53] S. Chowdhury, S. Castro, C. Coker, T. E. Hinchliffe, N. Arpaia, and T. Danino, “Programmable Bacteria Induce Durable Tumor Regression and Systemic Antitumor Immunity,” Nature Medicine 25 (2019): 1057-1063.

[54] M. Xie, H. Ye, H. Wang, et al., “β-cell-Mimetic Designer Cells Provide Closed-Loop Glycemic Control,” Science 354 (2016): 1296-1301.

[55] G. M. Allen, N. W. Frankel, N. R. Reddy, et al., “Synthetic Cytokine Circuits That Drive T Cells into Immune-Excluded Tumors,” Science 378 (2022): eaba1624.

[56] J. Zhou, M. Li, Q. Chen, et al., “Programmable Probiotics Modulate Inflammation and Gut Microbiota for Inflammatory Bowel Disease Treatment after Effective Oral Delivery,” Nature Communications 13 (2022): 3432.

[57] C. Yang, M. Cui, Y. Zhang, et al., “Upconversion Optogenetic Micro-Nanosystem Optically Controls the Secretion of Light-Responsive Bacteria for Systemic Immunity Regulation,” Communications Biology 3 (2020): 561.

[58] Y. Chen, M. Du, Z. Yuan, Z. Chen, and F. Yan, “Spatiotemporal Control of Engineered Bacteria to Express Interferon-γ by Focused Ultrasound for Tumor Immunotherapy,” Nature Communications 13 (2022): 4468.

[59] X. Ma, X. Liang, Y. Li, et al., “Modular-Designed Engineered Bacteria for Precision Tumor Immunotherapy via Spatiotemporal Manipulation by Magnetic Field,” Nature Communications 14 (2023): 1606.

[60] K. Krawczyk, S. Xue, P. Buchmann, et al., “Electrogenetic Cellular Insulin Release for Real-Time Glycemic Control in Type 1 Diabetic Mice,” Science 368 (2020): 993-1001.

[61] J. Zhu, Y. Ke, Q. Liu, et al., “Engineered Lactococcus Lactis Secreting Flt3L and OX40 Ligand for in Situ Vaccination-Based Cancer Immunotherapy,” Nature Communications 13 (2022): 7466.

[62] Y. Yue, J. Xu, Y. Li, et al., “Antigen-bearing Outer Membrane Vesicles as Tumour Vaccines Produced in Situ by Ingested Genetically Engineered Bacteria,” Nature Biomedical Engineering 6 (2022): 898-909.

[63] W. Shi, X. Yang, S. Xie, et al., “A New PD-1-Specific Nanobody Enhances the Antitumor Activity of T-Cells in Synergy with Dendritic Cell Vaccine,” Cancer Letters 522 (2021): 184-197.

[64] M. H. Linde, A. C. Fan, T. Köhnke, et al., “Reprogramming Cancer Into Antigen-Presenting Cells as a Novel Immunotherapy,” Cancer Discovery 13 (2023): 1164-1185.

[65] A. V. R. Kornepati, R. K. Vadlamudi, and T. J. Curiel, “Programmed Death Ligand 1 Signals in Cancer Cells,” Nature Reviews Cancer 22 (2022): 174-189.

[66] K. M. Hargadon, C. E. Johnson, and C. J. Williams, “Immune Checkpoint Blockade Therapy for Cancer: An Overview of FDA-Approved Immune Checkpoint Inhibitors,” International Immunopharmacology 62 (2018): 29-39.

[67] L. Zhou, M. Zou, Y. Xu, P. Lin, C. Lei, and X. Xia, “Nano Drug Delivery System for Tumor Immunotherapy: Next-Generation Therapeutics,” Frontiers in Oncology 12 (2022): 864301.

[68] S. Li, Z. Lu, S. Wu, et al., “The Dynamic Role of Platelets in Cancer Progression and Their Therapeutic Implications,” Nature Reviews Cancer 24 (2024): 72-87.

[69] C. Wang, W. Sun, Y. Ye, Q. Hu, H. N. Bomba, and Z. Gu, “In Situ Activation of Platelets With Checkpoint Inhibitors for Post-Surgical Cancer Immunotherapy,” Nature Biomedical Engineering 1 (2017): 0011.

[70] Q. Hu, H. Li, E. Archibong, et al., “Inhibition of Post-Surgery Tumour Recurrence via a Hydrogel Releasing CAR-T Cells and Anti-PDL1-Conjugated Platelets,” Nature Biomedical Engineering 5 (2021): 1038-1047.

[71] J. Fang, N. Ding, X. Guo, et al., “αPD-1-mesoCAR-T Cells Partially Inhibit the Growth of Advanced/Refractory Ovarian Cancer in a Patient along With Daily Apatinib,” Journal for ImmunoTherapy of Cancer 9 (2021): e001162.

[72] M. Mansouri and M. Fussenegger, “Therapeutic Cell Engineering: Designing Programmable Synthetic Genetic Circuits in Mammalian Cells,” Protein Cell 13 (2022): 476-489.

[73] M. Xie, V. Haellman, and M. Fussenegger, “Synthetic Biology — Application-Oriented Cell Engineering,” Current Opinion in Biotechnology 40 (2016): 139-148.

[74] K. Rössger, G. Charpin-El-Hamri, and M. Fussenegger, “A Closed-Loop Synthetic Gene Circuit for the Treatment of Diet-Induced Obesity in Mice,” Nature Communications 4 (2013): 2825.

[75] Y. Liu, P. Bai, A. K. Woischnig, et al., “Immunomimetic Designer Cells Protect Mice From MRSA Infection,” Cell 174 (2018): 259-270.

[76] J. Li, N. Li, J. Wei, et al., “Genetically Engineered Mesenchymal Stem Cells with Dopamine Synthesis for Parkinson's Disease in Animal Models,” Npj Parkinson's Disease 8 (2022): 175.

[77] H. Wang, C. N. Alarcón, B. Liu, et al., “Genetically Engineered and Enucleated Human Mesenchymal Stromal Cells for the Targeted Delivery of Therapeutics to Diseased Tissue,” Nature Biomedical Engineering 6 (2022): 882-897.

[78] T. Lan, L. Chen, and X. Wei, “Inflammatory Cytokines in Cancer: Comprehensive Understanding and Clinical Progress in Gene Therapy,” Cells 10 (2021): 100.

[79] Z. Zhang, L. Miao, Z. Ren, F. Tang, and Y. Li, “Gene-Edited Interleukin CAR-T Cells Therapy in the Treatment of Malignancies: Present and Future,” Frontiers in Immunology 12 (2021): 718686.

[80] M. Bell and S. Gottschalk, “Engineered Cytokine Signaling to Improve CAR T Cell Effector Function,” Frontiers in Immunology 12 (2021): 684642.

[81] X. Ma, P. Shou, C. Smith, et al., “Interleukin-23 Engineering Improves CAR T Cell Function in Solid Tumors,” Nature Biotechnology 38 (2020): 448-459.

[82] Y. Zhao, J. Chen, M. Andreatta, et al., “IL-10-Expressing CAR T Cells Resist Dysfunction and Mediate Durable Clearance of Solid Tumors and Metastases,” Nature Biotechnology 42 (2024): 1693-1704.

[83] S. Kaczanowska, D. W. Beury, V. Gopalan, et al., “Genetically Engineered Myeloid Cells Rebalance the Core Immune Suppression Program in Metastasis,” Cell 184 (2021): 2033-2052.

[84] C. Jin, J. Ma, M. Ramachandran, D. Yu, and M. Essand, “Car T Cells Expressing a Bacterial Virulence Factor Trigger Potent Bystander Antitumour Responses in Solid Cancers,” Nature Biomedical Engineering 6 (2022): 830-841.

[85] A. Ghasemi, A. Martinez-Usatorre, L. Li, et al., “Cytokine-Armed Dendritic Cell Progenitors for Antigen-Agnostic Cancer Immunotherapy,” Nature Cancer 5 (2024): 240-261.

[86] K. C. Valkenburg, A. E. de Groot, and K. J. Pienta, “Targeting the Tumour Stroma to Improve Cancer Therapy,” Nature Reviews Clinical Oncology 15 (2018): 366-381.

[87] Y. He, T. Liu, S. Dai, Z. Xu, L. Wang, and F. Luo, “Tumor-Associated Extracellular Matrix: How to Be a Potential Aide to Anti-Tumor Immunotherapy?,” Frontiers in Cell and Developmental Biology 9 (2021): 739161.

[88] Y. Zhao, Y. Dong, S. Yang, et al., “Bioorthogonal Equipping CAR-T Cells With Hyaluronidase and Checkpoint Blocking Antibody for Enhanced Solid Tumor Immunotherapy,” ACS Central Science 8 (2022): 603-614.

[89] Z. Xiao, L. Todd, L. Huang, et al., “Desmoplastic Stroma Restricts T Cell Extravasation and Mediates Immune Exclusion and Immunosuppression in Solid Tumors,” Nature Communications 14 (2023): 5110.

[90] J. Wang, Y. Dong, P. Ma, et al., “Intelligent Micro-/Nanorobots for Cancer Theragnostic,” Advanced Materials 34 (2022): e2201051.

[91] J. Li, B. Esteban-Fernández de Ávila, W. Gao, L. Zhang, and J. Wang, “Micro/Nanorobots for Biomedicine: Delivery, Surgery, Sensing, and Detoxification,” Science Robotics 2 (2017): eaam6431.

[92] W. Hu, Q. Li, B. Li, K. Ma, C. Zhang, and X. Fu, “Optogenetics Sheds New Light on Tissue Engineering and Regenerative Medicine,” Biomaterials 227 (2020): 119546.

[93] Z. Zhao, Q. Saiding, Z. Cai, M. Cai, and W. Cui, “Ultrasound Technology and Biomaterials for Precise Drug Therapy,” Materials Today 63 (2023): 210-238.

[94] M. Christiansen, W. Hornslien, and S. Schurle, “A Possible Inductive Mechanism for Magnetogenetics,” Biorxiv 20200716207126 (2020).

[95] S. A. Stanley, L. Kelly, K. N. Latcha, et al., “Bidirectional Electromagnetic Control of the Hypothalamus Regulates Feeding and Metabolism,” Nature 531 (2016): 647-650.

[96] B. Hasannejad-Asl, F. Pooresmaeil, S. Takamoli, M. Dabiri, and A. Bolhassani, “Cell-Penetrating Peptide: A Potent Delivery System in Vaccine Development,” Frontiers in Pharmacology 13 (2022): 1072685.

[97] S. Jhunjhunwala, C. Hammer, and L. Delamarre, “Antigen Presentation in Cancer: Insights into Tumour Immunogenicity and Immune Evasion,” Nature Reviews Cancer 21 (2021): 298-312.

[98] R. Zhang, X. Peng, G. Duan, et al., “An Engineered Lactococcus Lactis Strain Exerts Significant Immune Responses through Efficient Expression and Delivery of Helicobacter Pylori Lpp20 Antigen,” Biotechnology Letters 38 (2016): 2169-2175.

[99] V. Chamcha, A. Jones, B. R. Quigley, J. R. Scott, and R. R. Amara, “Oral Immunization With a Recombinant Lactococcus Lactis -Expressing HIV-1 Antigen on Group A Streptococcus Pilus Induces Strong Mucosal Immunity in the Gut,” Journal of Immunology 195 (2015): 5025-5034.

[100] M. Super, E. J. Doherty, M. J. Cartwright, et al., “Biomaterial Vaccines Capturing Pathogen-Associated Molecular Patterns Protect against Bacterial Infections and Septic Shock,” Nature Biomedical Engineering 6 (2022): 8-18.

[101] Y. E. Chen, D. Bousbaine, A. Veinbachs, et al., “Engineered Skin Bacteria Induce Antitumor T Cell Responses against Melanoma,” Science 380 (2023): 203-210.

[102] R. L. Vincent, C. R. Gurbatri, F. Li, et al., “Probiotic-Guided CAR-T Cells for Solid Tumor Targeting,” Science 382 (2023): 211-218.

[103] A. Harari, M. Graciotti, M. Bassani-Sternberg, and L. E. Kandalaft, “Antitumour Dendritic Cell Vaccination in a Priming and Boosting Approach,” Nature Reviews Drug Discovery 19 (2020): 635-652.

[104] M. Collin and V. Bigley, “Human Dendritic Cell Subsets: An Update,” Immunology 154 (2018): 3-20.

[105] R. L. Prue, F. Vari, K. J. Radford, et al., “A Phase I Clinical Trial of CD1c (BDCA-1)+ Dendritic Cells Pulsed with HLA-A*0201 Peptides for Immunotherapy of Metastatic Hormone Refractory Prostate Cancer,” Journal of Immunotherapy 38 (2015): 71-76.

[106] H. Westdorp, J. H. A. Creemers, I. M. van Oort, et al., “Blood-Derived Dendritic Cell Vaccinations Induce Immune Responses That Correlate With Clinical Outcome in Patients With Chemo-Naive Castration-Resistant Prostate Cancer,” Journal for ImmunoTherapy of Cancer 7 (2019): 302.

[107] J. L. Hsu, C. E. Bryant, M. S. Papadimitrious, et al., “A Blood Dendritic Cell Vaccine for Acute Myeloid Leukemia Expands Anti-Tumor T Cell Responses at Remission,” Oncoimmunology 7 (2018): e1419114.

[108] V. Koucký, J. Bouček, and A. Fialová, “Immunology of Plasmacytoid Dendritic Cells in Solid Tumors: A Brief Review,” Cancers 11 (2019): 470.

[109] S. Lee, S. Kivimäe, A. Dolor, and F. C. Szoka, “Macrophage-Based Cell Therapies: The Long and Winding Road,” Journal of Controlled Release 240 (2016): 527-540.

[110] O. Zimmermannova, A. G. Ferreira, E. Ascic, et al., “Restoring Tumor Immunogenicity With Dendritic Cell Reprogramming,” Science Immunology 8 (2023): eadd4817.

[111] E. A. Scott, N. B. Karabin, and P. Augsornworawat, “Overcoming Immune Dysregulation With Immunoengineered Nano-Biomaterials,” Annual Review of Biomedical Engineering 19 (2017): 57-84.

[112] M. S. Goldberg, “Improving Cancer Immunotherapy through Nanotechnology,” Nature Reviews Cancer 19 (2019): 587-602.

[113] E. P. Stater, A. Y. Sonay, C. Hart, and J. Grimm, “The Ancillary Effects of Nanoparticles and Their Implications for Nanomedicine,” Nature Nanotechnology 16 (2021): 1180-1194.

[114] P. J. Gawne, M. Ferreira, M. Papaluca, J. Grimm, and P. Decuzzi, “New Opportunities and Old Challenges in the Clinical Translation of Nanotheranostics,” Nature Reviews Materials 8 (2023): 783-798.

[115] B. B. Mendes, J. Conniot, A. Avital, et al., “Nanodelivery of Nucleic Acids,” Nature Reviews Methods Primers 2 (2022): 24.

[116] G. Liu, M. Zhu, X. Zhao, and G. Nie, “Nanotechnology-Empowered Vaccine Delivery for Enhancing CD8+ T Cells-Mediated Cellular Immunity,” Advanced Drug Delivery Reviews 176 (2021): 113889.

[117] A. S. Cheung, D. K. Y. Zhang, S. T. Koshy, and D. J. Mooney, “Scaffolds That Mimic Antigen-Presenting Cells Enable Ex Vivo Expansion of Primary T Cells,” Nature Biotechnology 36 (2018): 160-169.

[118] P. Agarwalla, E. A. Ogunnaike, S. Ahn, et al., “Bioinstructive Implantable Scaffolds for Rapid in Vivo Manufacture and Release of CAR-T Cells,” Nature Biotechnology 40 (2022): 1250-1258.

[119] C. Chen, W. Jing, Y. Chen, et al., “Intracavity Generation of Glioma Stem Cell-Specific Car Macrophages Primes Locoregional Immunity for Postoperative Glioblastoma Therapy,” Science Translational Medicine 14 (2022): eabn1128.

[120] S. Ling, S. Yang, X. Hu, et al., “Lentiviral Delivery of Co-Packaged Cas9 MRNA and a VEGFA-Targeting Guide RNA Prevents Wet Age-Related Macular Degeneration in Mice,” Nature Biomedical Engineering 5 (2021): 144-156.

[121] L. Breda, T. E. Papp, M. P. Triebwasser, et al., “In Vivo Hematopoietic Stem Cell Modification by MRNA Delivery,” Science 381 (2023): 436-443.

[122] X. Tang, Y. Yang, M. Zheng, et al., “Magnetic-Acoustic Sequentially Actuated CAR T Cell Microrobots for Precision Navigation and in Situ Antitumor Immunoactivation,” Advanced Materials 35 (2023): e2211509.

[123] Y. Luo, Z. Chen, M. Sun, et al., “IL-12 Nanochaperone-Engineered CAR T Cell for Robust Tumor-Immunotherapy,” Biomaterials 281 (2022): 121341.

[124] M.-H. Zhu, X.-D. Zhu, M. Long, et al., “Metal-Coordinated Adsorption of Nanoparticles to Macrophages for Targeted Cancer Therapy,” Advanced Functional Materials 33 (2023): 2214842.

[125] Y. Dai, X. Bai, L. Jia, et al., “Precise Control of Customized Macrophage Cell Robot for Targeted Therapy of Solid Tumors With Minimal Invasion,” Small 17 (2021): e2103986.

[126] Y. Chang, X. Cai, R. Syahirah, et al., “CAR-Neutrophil Mediated Delivery of Tumor-Microenvironment Responsive Nanodrugs for Glioblastoma Chemo-Immunotherapy,” Nature Communications 14 (2023): 2266.

[127] H. Zhang, Z. Li, C. Gao, et al., “Dual-Responsive Biohybrid Neutrobots for Active Target Delivery,” Science Robotics 6 (2021): eaaz9519.

[128] Z. Luo, Y. Lu, Y. Shi, et al., “Neutrophil Hitchhiking for Drug Delivery to the Bone Marrow,” Nature Nanotechnology 18 (2023): 647-656.

[129] L. Zhang, B. Zhang, R. Liang, et al., “A Dual-Biomineralized Yeast Micro-/Nanorobot With Self-Driving Penetration for Gastritis Therapy and Motility Recovery,” ACS Nano 17 (2023): 6410-6422.

[130] F. Zhang, J. Zhuang, Z. Li, et al., “Nanoparticle-Modified Microrobots for in Vivo Antibiotic Delivery to Treat Acute Bacterial Pneumonia,” Nature Materials 21 (2022): 1324-1332.

[131] L. Wang, G. Wang, W. Mao, et al., “Bioinspired Engineering of Fusogen and Targeting Moiety Equipped Nanovesicles,” Nature Communications 14 (2023): 3366.

[132] W. Fang, L. Li, Z. Lin, et al., “Engineered IL-15/IL-15R α-Expressing Cellular Vesicles Promote T Cell Anti-Tumor Immunity,” Extracellular Vesicle 2 (2023): 100021.

[133] T. Fang, B. Li, M. Li, et al., “Engineered Cell Membrane Vesicles Expressing CD40 Alleviate System Lupus Nephritis by Intervening B Cell Activation,” Small Methods 7 (2023): e2200925.

[134] Y. Yu, Q. Cheng, X. Ji, et al., “Engineered Drug-Loaded Cellular Membrane Nanovesicles for Efficient Treatment of Postsurgical Cancer Recurrence and Metastasis,” Science Advances 8 (2022): eadd3599.

[135] X. Shi, Q. Cheng, T. Hou, et al., “Genetically Engineered Cell-Derived Nanoparticles for Targeted Breast Cancer Immunotherapy,” Molecular Therapy 28 (2020): 536.

[136] Q. Cheng, Z. Dai, G. Smbatyan, et al., “Eliciting Anti-Cancer Immunity by Genetically Engineered Multifunctional Exosomes,” Molecular Therapy 30 (2022): 3066-3077.

[137] R. Bhatta, J. Han, Y. Liu, et al., “Metabolic Tagging of Extracellular Vesicles and Development of Enhanced Extracellular Vesicle Based Cancer Vaccines,” Nature Communications 14 (2023): 8047.

[138] K. Cheng, R. Zhao, Y. Li, et al., “Bioengineered Bacteria-Derived Outer Membrane Vesicles as a Versatile Antigen Display Platform for Tumor Vaccination via Plug-and-Display Technology,” Nature Communications 12 (2021): 2041.

[139] Y. Li, X. Ma, Y. Yue, et al., “Rapid Surface Display of mRNA Antigens by Bacteria-Derived Outer Membrane Vesicles for a Personalized Tumor Vaccine,” Advanced Materials 34 (2022): e2109984.

[140] Y. Li, R. Zhao, K. Cheng, et al., “Bacterial Outer Membrane Vesicles Presenting Programmed Death 1 for Improved Cancer Immunotherapy via Immune Activation and Checkpoint Inhibition,” ACS Nano 14 (2020): 16698-16711.

[141] S. Li, Q. Jiang, S. Liu, et al., “A DNA Nanorobot Functions as a Cancer Therapeutic in Response to a Molecular Trigger in Vivo,” Nature Biotechnology 36 (2018): 258-264.

[142] W. Tang, T. Tong, H. Wang, et al., “A DNA Origami-Based Gene Editing System for Efficient Gene Therapy in Vivo,” Angewandte Chemie International Edition 62 (2023): e202315093.

[143] Z. Xu, Y. Dong, N. Ma, et al., “Confinement in Dual-Chain-Locked DNA Origami Nanocages Programs Marker-Responsive Delivery of CRISPR/Cas9 Ribonucleoproteins,” Journal of the American Chemical Society 145 (2023): 26557-26568.

[144] Z. Wang, S. Zhang, R. Zhang, et al., “Bioengineered Dual-Targeting Protein Nanocage for Stereoscopical Loading of Synergistic Hydrophilic/Hydrophobic Drugs to Enhance Anticancer Efficacy,” Advanced Functional Materials 31 (2021): 2102004.

[145] H. Huang, S. Yuan, Z. Ma, et al., “Genetic Recombination of Poly( L-Lysine) Functionalized Apoferritin Nanocages That Resemble Viral Capsid Nanometer-Sized Platforms for Gene Therapy,” Biomaterials Science 8 (2020): 1759-1770.

[146] Y. Wu, H. Xie, Y. Li, et al., “Nitric Oxide-Loaded Bioinspired Lipoprotein Normalizes Tumor Vessels to Improve Intratumor Delivery and Chemotherapy of Albumin-Bound Paclitaxel Nanoparticles,” Nano Letters 23 (2023): 939-947.

[147] Y. Zhai, J. Wang, T. Lang, et al., “T Lymphocyte Membrane-Decorated Epigenetic Nanoinducer of Interferons for Cancer Immunotherapy,” Nature Nanotechnology 16 (2021): 1271-1280.

[148] Q. Tang, S. Sun, P. Wang, et al., “Genetically Engineering Cell Membrane-Coated BTO Nanoparticles for MMP2-Activated Piezocatalysis-Immunotherapy,” Advanced Materials 35 (2023): e2300964.

[149] S. Koo, H. S. Sohn, T. H. Kim, et al., “Ceria-Vesicle Nanohybrid Therapeutic for Modulation of Innate and Adaptive Immunity in a Collagen-Induced Arthritis Model,” Nature Nanotechnology 18 (2023): 1502-1514.

[150] C. Simó, M. Serra-Casablancas, A. C. Hortelao, et al., “Urease-Powered Nanobots for Radionuclide Bladder Cancer Therapy,” Nature Nanotechnology 19 (2024): 554-564.

[151] M. Yan, Q. Chen, T. Liu, et al., “Site-Selective Superassembly of Biomimetic Nanorobots Enabling Deep Penetration Into Tumor With Stiff Stroma,” Nature Communications 14 (2023): 4628.

[152] N. Yin, W. Zhang, X. X. Sun, et al., “Artificial Cells Delivering Itaconic Acid Induce Anti-Inflammatory Memory-Like Macrophages to Reverse Acute Liver Failure and Prevent Reinjury,” Cell Reports Medicine 4 (2023): 101132.

[153] R. Liu, W. Wang, Y. Wang, L. Zhang, and G. Chen, “The Preliminary Study on Preparation Technology of PolyHb-SOD-CATCA—The Effects of Different Extractants,” Current Pharmaceutical Biotechnology 24 (2023): 1928-1937.

[154] Y. Ma, H. Yang, X. Zong, et al., “Artificial M2 Macrophages for Disease-Modifying Osteoarthritis Therapeutics,” Biomaterials 274 (2021): 120865.

[155] P. Xiao, J. Wang, Z. Zhao, et al., “Engineering Nanoscale Artificial Antigen-Presenting Cells by Metabolic Dendritic Cell Labeling to Potentiate Cancer Immunotherapy,” Nano Letters 21 (2021): 2094-2103.

[156] D. J. Irvine, M. V. Maus, D. J. Mooney, and W. W. Wong, “The Future of Engineered Immune Cell Therapies,” Science 378 (2022): 853-858.

[157] H. S. Kim, T. C. Ho, M. J. Willner, M. W. Becker, H. W. Kim, and K. W. Leong, “Dendritic Cell-Mimicking Scaffolds for Ex Vivo T Cell Expansion,” Bioactive Materials 21 (2023): 241-252.

[158] D. H. Gutmann and H. Kettenmann, “Microglia/Brain Macrophages as Central Drivers of Brain Tumor Pathobiology,” Neuron 104 (2019): 442-449.

[159] C. Garris and M. J. Pittet, “Therapeutically Reeducating Macrophages to Treat GBM,” Nature Medicine 19 (2013): 1207-1208.

[160] J. H. Sampson, M. D. Gunn, P. E. Fecci, and D. M. Ashley, “Brain Immunology and Immunotherapy in Brain Tumours,” Nature Reviews Cancer 20 (2020): 12-25.

[161] H. Wang, M. C. Sobral, D. K. Y. Zhang, et al., “Metabolic Labeling and Targeted Modulation of Dendritic Cells,” Nature Materials 19 (2020): 1244-1252.

[162] H. Du, J. M. Bartleson, S. Butenko, et al., “Tuning Immunity through Tissue Mechanotransduction,” Nature Reviews Immunology 23 (2023): 174-188.

[163] K. Lei, A. Kurum, M. Kaynak, et al., “Cancer-Cell Stiffening via Cholesterol Depletion Enhances Adoptive T-Cell Immunotherapy,” Nature Biomedical Engineering 5 (2021): 1411-1425.

[164] W. A. Nyberg, J. Ark, A. To, et al., “An Evolved AAV Variant Enables Efficient Genetic Engineering of Murine T Cells,” Cell 186 (2023): 446-460.

[165] T. Kerzel, G. Giacca, S. Beretta, et al., “In Vivo Macrophage Engineering Reshapes the Tumor Microenvironment Leading to Eradication of Liver Metastases,” Cancer Cell 41 (2023): 1892-1910.

[166] A. D. Nahmad, C. R. Lazzarotto, N. Zelikson, et al., “In Vivo Engineered B Cells Secrete High Titers of Broadly Neutralizing Anti-HIV Antibodies in Mice,” Nature Biotechnology 40 (2022): 1241-1249.

[167] D. Yin, S. Ling, D. Wang, et al., “Targeting Herpes Simplex Virus with CRISPR-Cas9 Cures Herpetic Stromal Keratitis in Mice,” Nature Biotechnology 39 (2021): 567-577.

[168] S. Banskota, A. Raguram, S. Suh, et al., “Engineered Virus-Like Particles for Efficient in Vivo Delivery of Therapeutic Proteins,” Cell 185 (2022): 250-265.

[169] M. An, A. Raguram, S. W. Du, et al., “Engineered Virus-Like Particles for Transient Delivery of Prime Editor Ribonucleoprotein Complexes in Vivo,” Nature Biotechnology 185 (2024): 250-265.

[170] C. J. Bao, J. L. Duan, Y. Xie, et al., “Bioorthogonal Engineered Virus-Like Nanoparticles for Efficient Gene Therapy,” Nano-Micro Letters 15 (2023): 197.

[171] J. R. Hamilton, E. Chen, B. S. Perez, et al., “In Vivo Human T Cell Engineering With Enveloped Delivery Vehicles,” Nature Biotechnology 185 (2024): 250-265.

[172] S. A. Dilliard, Q. Cheng, and D. J. Siegwart, “On the Mechanism of Tissue-Specific mRNA Delivery by Selective Organ Targeting Nanoparticles,” Proceedings of the National Academy of Sciences of the United States of America 118 (2021): e2109256118.

[173] Q. Cheng, T. Wei, L. Farbiak, L. T. Johnson, S. A. Dilliard, and D. J. Siegwart, “Selective Organ Targeting (Sort) Nanoparticles for Tissue-Specific mRNA Delivery and CRISPR-CAS Gene Editing,” Nature Nanotechnology 15 (2020): 313-320.

[174] L. M. Kranz, M. Diken, H. Haas, et al., “Systemic RNA Delivery to Dendritic Cells Exploits Antiviral Defence for Cancer Immunotherapy,” Nature 534 (2016): 396-401.

[175] J. G. Rurik, I. Tombácz, A. Yadegari, et al., “CAR T Cells Produced in Vivo to Treat Cardiac Injury,” Science 375 (2022): 91-96.

[176] M. Yu, W. Song, F. Tian, et al., “Temperature- and Rigidity-Mediated Rapid Transport of Lipid Nanovesicles in Hydrogels,” Proceedings of the National Academy of Sciences of the United States of America 116 (2019): 5362-5369.

[177] Z. Belhadj, Y. Qie, R. P. Carney, Y. Li, and G. Nie, “Current Advances in Non-Viral Gene Delivery Systems: Liposomes versus Extracellular Vesicles,” BMEMat 1 (2023): e12018.

[178] S. Liu, Q. Cheng, T. Wei, et al., “Membrane-Destabilizing Ionizable Phospholipids for Organ-Selective mRNA Delivery and CRISPR-Cas Gene Editing,” Nature Materials 20 (2021): 701-710.

[179] F. Ma, L. Yang, Z. Sun, J. Chen, X. Rui, Z. Glass, and Q. Xu, “Neurotransmitter-Derived Lipidoids (NT-lipidoids) for Enhanced Brain Delivery through Intravenous Injection,” Science Advances 6 (2020): eabb4429.

[180] H. Li, Y. Tong, L. Bai, L. Ye, L. Zhong, X. Duan, and Y. Zhu, “Lactoferrin Functionalized PEG-PLGA Nanoparticles of Shikonin for Brain Targeting Therapy of Glioma,” International Journal of Biological Macromolecules 107 (2018): 204-211.

[181] D. E. Tylawsky, H. Kiguchi, J. Vaynshteyn, et al., “P-Selectin-Targeted Nanocarriers Induce Active Crossing of the Blood-Brain Barrier via Caveolin-1-Dependent Transcytosis,” Nature Materials 22 (2023): 391-399.

[182] S. Liu, X. Wang, X. Yu, et al., “Zwitterionic Phospholipidation of Cationic Polymers Facilitates Systemic mRNA Delivery to Spleen and Lymph Nodes,” Journal of the American Chemical Society 143 (2021): 21321-21330.

[183] L. Alvarez-Erviti, Y. Seow, H. Yin, C. Betts, S. Lakhal, and M. J. A. Wood, “Delivery of siRNA to the Mouse Brain by Systemic Injection of Targeted Exosomes,” Nature Biotechnology 29 (2011): 341-345.

[184] L. Ortega-Pineda, A. Sunyecz, A. I. Salazar-Puerta, et al., “Designer Extracellular Vesicles Modulate Pro-Neuronal Cell Responses and Improve Intracranial Retention,” Advanced Healthcare Materials 11 (2022): e2100805.

[185] Z. Hosseinidoust, B. Mostaghaci, O. Yasa, B. W. Park, A. V. Singh, and M. Sitti, “Bioengineered and Biohybrid Bacteria-Based Systems for Drug Delivery,” Advanced Drug Delivery Reviews 106 (2016): 27-44.

[186] O. Felfoul, M. Mohammadi, S. Taherkhani, et al., “Magneto-Aerotactic Bacteria Deliver Drug-Containing Nanoliposomes to Tumour Hypoxic Regions,” Nature Nanotechnology 11 (2016): 941-947.

[187] M. B. Akolpoglu, Y. Alapan, N. O. Dogan, et al., “Magnetically Steerable Bacterial Microrobots Moving in 3d Biological Matrices for Stimuli-Responsive Cargo Delivery,” Science Advances 8 (2022): eabo6163.

[188] H. Xu, M. Medina-Sánchez, M. F. Maitz, C. Werner, and O. G. Schmidt, “Sperm Micromotors for Cargo Delivery Through Flowing Blood,” ACS Nano 14 (2020): 2982-2993.

[189] Q. Chen, S. Tang, Y. Li, et al., “Multifunctional Metal-Organic Framework Exoskeletons Protect Biohybrid Sperm Microrobots for Active Drug Delivery from the Surrounding Threats,” ACS Applied Materials & Interfaces Journal 13 (2021): 58382-58392.

[190] F. Cao, L. Jin, Y. Gao, et al., “Artificial-Enzymes-Armed Bifidobacterium Longum Probiotics for Alleviating Intestinal Inflammation and Microbiota Dysbiosis,” Nature Nanotechnology 18 (2023): 617-627.

[191] J. Ali, U. K. Cheang, J. D. Martindale, M. Jabbarzadeh, H. C. Fu, and M. J. Kim, “Bacteria-Inspired Nanorobots With Flagellar Polymorphic Transformations and Bundling,” Scientific Reports 7 (2017): 14098.

[192] H. Xu, M. Medina-Sánchez, V. Magdanz, L. Schwarz, F. Hebenstreit, and O. G. Schmidt, “Sperm-Hybrid Micromotor for Targeted Drug Delivery,” ACS Nano 12 (2018): 327-337.

[193] T. Gwisai, N. Mirkhani, M. G. Christiansen, T. T. Nguyen, V. Ling, and S. Schuerle, “Magnetic Torque-Driven Living Microrobots for Increased Tumor Infiltration,” Science Robotics 7 (2022): eabo0665.

[194] S. Osuka and E. G. Van Meir, “Neutrophils Traffic in Cancer Nanodrugs,” Nature Nanotechnology 12 (2017): 616-618.

[195] Y. Chen, K. Li, M. Jiao, et al., “Reprogrammed siTNFα/Neutrophil Cytopharmaceuticals Targeting Inflamed Joints for Rheumatoid Arthritis Therapy,” Acta Pharmaceutica Sinica B 13 (2023): 787-803.

[196] J. Shao, M. Xuan, H. Zhang, X. Lin, Z. Wu, and Q. He, “Chemotaxis-Guided Hybrid Neutrophil Micromotors for Targeted Drug Transport,” Angewandte Chemie International Edition 56 (2017): 12935-12939.

[197] C. Martin, P. C. Burdon, G. Bridger, J. C. Gutierrez-Ramos, T. J. Williams, and S. M. Rankin, “Chemokines Acting via CXCR2 and CXCR4 Control the Release of Neutrophils From the Bone Marrow and Their Return Following Senescence,” Immunity 19 (2003): 583-593.

[198] J. Wang, M. Hossain, A. Thanabalasuriar, M. Gunzer, C. Meininger, and P. Kubes, “Visualizing the Function and Fate of Neutrophils in Sterile Injury and Repair,” Science 358 (2017): 111-116.

[199] H. Garner and K. E. de Visser, “Neutrophils Take a Round-Trip,” Science 358 (2017): 42-43.

[200] J. Xue, Z. Zhao, L. Zhang, et al., “Neutrophil-Mediated Anticancer Drug Delivery for Suppression of Postoperative Malignant Glioma Recurrence,” Nature Nanotechnology 12 (2017): 692-700.

[201] Z. Gao, N. Wang, Y. Ma, et al., “Targeting Neutrophils Potentiates Hitchhiking Delivery of Drugs and Agonists for Postsurgical Chemo-Immunotherapy,” Nano Today 54 (2024): 102096.

[202] M. Li, S. Li, H. Zhou, et al., “Chemotaxis-Driven Delivery of Nano-Pathogenoids for Complete Eradication of Tumors Post-Phototherapy,” Nature Communications 11 (2020): 1126.

[203] J. Kuang, Z.-Y. Rao, D.-W. Zheng, et al., “Nanoparticles Hitchhike on Monocytes for Glioblastoma Treatment After Low-Dose Radiotherapy,” ACS Nano 17 (2023): 13333-13347.

[204] L. Zheng, X. Hu, H. Wu, et al., “In Vivo Monocyte/Macrophage-Hitchhiked Intratumoral Accumulation of Nanomedicines for Enhanced Tumor Therapy,” Journal of the American Chemical Society 142 (2020): 382-391.

[205] F. Zhang, Z. Li, Y. Duan, et al., “Gastrointestinal Tract Drug Delivery Using Algae Motors Embedded in a Degradable Capsule,” Science Robotics 7 (2022): eabo4160.

[206] Z. Chen, H. Pan, Y. Luo, et al., “Nanoengineered CAR-T Biohybrids for Solid Tumor Immunotherapy With Microenvironment Photothermal-Remodeling Strategy,” Small 17 (2021): e2007494.

[207] L. Tang, Y. Zheng, M. B. Melo, et al., “Enhancing T Cell Therapy through TCR-Signaling-Responsive Nanoparticle Drug Delivery,” Nature Biotechnology 36 (2018): 707-716.

[208] C. W. Shields, M. A. Evans, L. L. Wang, et al., “Cellular Backpacks for Macrophage Immunotherapy,” Science Advances 6 (2020): eaaz6579.

[209] C. X. Li, Y. Zhang, X. Dong, et al., “Artificially Reprogrammed Macrophages as Tumor-Tropic Immunosuppression-Resistant Biologics to Realize Therapeutics Production and Immune Activation,” Advanced Materials 31 (2019): e1807211.

[210] F. Zhang, Z. Li, L. Yin, et al., “ACE2 Receptor-Modified Algae-Based Microrobot for Removal of SARS-CoV-2 in Wastewater,” Journal of the American Chemical Society 143 (2021): 12194-12201.

[211] J. Lai, Q. F. Meng, M. Tian, et al., “A Decoy Microrobot That Removes SARS-CoV-2 and Its Variants in Wastewater,” Cell Reports Physical Science 3 (2022): 101061.

[212] B. Mostaghaci, O. Yasa, J. Zhuang, and M. Sitti, “Bioadhesive Bacterial Microswimmers for Targeted Drug Delivery in the Urinary and Gastrointestinal Tracts,” Advanced Science 4 (2017): 1700058.

[213] W. Yang, Y. Bai, Y. Xiong, et al., “Potentiating the Antitumour Response of CD8+ T Cells by Modulating Cholesterol Metabolism,” Nature 531 (2016): 651-655.

[214] S. A. Lim, W. Su, N. M. Chapman, and H. Chi, “Lipid Metabolism in T Cell Signaling and Function,” Nature Chemical Biology 18 (2022): 470-481.

[215] M. Hao, S. Hou, W. Li, et al., “Combination of Metabolic Intervention and T Cell Therapy Enhances Solid Tumor Immunotherapy,” Science Translational Medicine 12 (2020): eaaz6667.

[216] C. Shi, Q. Zhang, Y. Yao, et al., “Targeting the Activity of T Cells by Membrane Surface Redox Regulation for Cancer Theranostics,” Nature Nanotechnology 18 (2023): 86-97.

[217] Q. Yang, R. Liu, Q. Yu, Y. Bi, and G. Liu, “Metabolic Regulation of Inflammasomes in Inflammation,” Immunology 157 (2019): 95-109.

[218] D. W. Zheng, L. Xu, C. X. Li, et al., “Photo-Powered Artificial Organelles for ATP Generation and Life-Sustainment,” Advanced Materials 30 (2018): e1805038.

[219] J. M. Diaz, C. M. Hansel, B. M. Voelker, C. M. Mendes, P. F. Andeer, and T. Zhang, “Widespread Production of Extracellular Superoxide by Heterotrophic Bacteria,” Science 340 (2013): 1223-1226.

[220] P. Chen, X. Liu, C. Gu, et al., “A Plant-Derived Natural Photosynthetic System for Improving Cell Anabolism,” Nature 612 (2022): 546-554.

[221] R. Yang, J. Xu, L. Xu, et al., “Cancer Cell Membrane-Coated Adjuvant Nanoparticles With Mannose Modification for Effective Anticancer Vaccination,” ACS Nano 12 (2018): 5121-5129.

[222] O. P. Wiklander, J. Z. Nordin, A. O'Loughlin, et al., “Extracellular Vesicle in Vivo Biodistribution Is Determined by Cell Source, Route of Administration and Targeting,” Journal of Extracellular Vesicles 4 (2015): 26316.

[223] D. Ingato, J. U. Lee, S. J. Sim, and Y. J. Kwon, “Good Things Come in Small Packages: Overcoming Challenges to Harness Extracellular Vesicles for Therapeutic Delivery,” Journal of Controlled Release 241 (2016): 174-185.

[224] T. Xue, Z. Zhang, T. Fang, et al., “Cellular Vesicles Expressing PD-1-Blocking scFv Reinvigorate T Cell Immunity against Cancer,” Nano Research 15 (2022): 5295-5304.

[225] L. Ding, X. Zhang, P. Yu, et al., “Genetically Engineered Nanovesicles Mobilize Synergistic Antitumor Immunity by ADAR1 Silence and PDL1 Blockade,” Molecular Therapy 31 (2023): 2489-2506.

[226] C. Liu, X. Liu, X. Xiang, et al., “A Nanovaccine for Antigen Self-Presentation and Immunosuppression Reversal as a Personalized Cancer Immunotherapy Strategy,” Nature Nanotechnology 17 (2022): 531-540.

[227] K. Wang, X. Zhang, H. Ye, et al., “Biomimetic Nanovaccine-Mediated Multivalent IL-15 Self-Transpresentation (MIST) for Potent and Safe Cancer Immunotherapy,” Nature Communications 14 (2023): 6748.

[228] L. Rao, S. Xia, W. Xu, et al., “Decoy Nanoparticles Protect against COVID-19 by Concurrently Adsorbing Viruses and Inflammatory Cytokines,” Proceedings of the National Academy of Sciences of the United States of America 117 (2020): 27141-27147.

[229] L. Cheng and A. F. Hill, “Therapeutically Harnessing Extracellular Vesicles,” Nature Reviews Drug Discovery 21 (2022): 379-399.

[230] H. Shao, H. Im, C. M. Castro, X. Breakefield, R. Weissleder, and H. Lee, “New Technologies for Analysis of Extracellular Vesicles,” Chemical Reviews 118 (2018): 1917-1950.

[231] L. Wang, D. Wang, Z. Ye, and J. Xu, “Engineering Extracellular Vesicles as Delivery Systems in Therapeutic Applications,” Advanced Science 10 (2023): e2300552.

[232] P. E. Martinez de Castilla, L. Tong, C. Huang, et al., “Extracellular Vesicles as a Drug Delivery System: A Systematic Review of Preclinical Studies,” Advanced Drug Delivery Reviews 175 (2021): 113801.

[233] X. Zhang, H. Cui, W. Zhang, Z. Li, and J. Gao, “Engineered Tumor Cell-Derived Vaccines against Cancer: The Art of Combating Poison With Poison,” Bioactive Materials 22 (2023): 491-517.

[234] M. Morishita, Y. Takahashi, A. Matsumoto, M. Nishikawa, and Y. Takakura, “Exosome-Based Tumor Antigens-Adjuvant Co-Delivery Utilizing Genetically Engineered Tumor Cell-Derived Exosomes with Immunostimulatory CpG DNA,” Biomaterials 111 (2016): 55-65.

[235] S. H. Kim, N. Bianco, R. Menon, E. R. Lechman, W. J. Shufesky, A. E. Morelli, and P. D. Robbins, “Exosomes Derived From Genetically Modified DC Expressing FasL Are Anti-inflammatory and Immunosuppressive,” Molecular Therapy 13 (2006): 289-300.

[236] C. Schwechheimer and M. J. Kuehn, “Outer-Membrane Vesicles From Gram-Negative Bacteria: Biogenesis and Functions,” Nature Reviews Microbiology 13 (2015): 605-619.

[237] C. Irene, L. Fantappiè, E. Caproni, et al., “Bacterial Outer Membrane Vesicles Engineered with Lipidated Antigens as a Platform for Staphylococcus Aureus Vaccine,” Proceedings of the National Academy of Sciences of the United States of America 116 (2019): 21780-21788.

[238] K. Kuipers, M. H. Daleke-Schermerhorn, W. S. Jong, et al., “Salmonella Outer Membrane Vesicles Displaying High Densities of Pneumococcal Antigen at the Surface Offer Protection against Colonization,” Vaccine 33 (2015): 2022-2029.

[239] M. L. Salverda, S. M. Meinderts, H. J. Hamstra, et al., “Surface Display of a Borrelial Lipoprotein on Meningococcal Outer Membrane Vesicles,” Vaccine 34 (2016): 1025-1033.

[240] O. Y. Kim, H. T. Park, N. T. H. Dinh, et al., “Bacterial Outer Membrane Vesicles Suppress Tumor by Interferon-Γ-Mediated Antitumor Response,” Nature Communications 8 (2017): 626.

[241] G. Liu, N. Ma, K. Cheng, et al., “Bacteria-Derived Nanovesicles Enhance Tumour Vaccination by Trained Immunity,” Nature Nanotechnology 19 (2024): 387-398.

[242] W. Ma, Y. Zhan, Y. Zhang, C. Mao, X. Xie, and Y. Lin, “The Biological Applications of DNA Nanomaterials: Current Challenges and Future Directions,” Signal Transduction and Targeted Therapy 6 (2021): 351.

[243] J. Wang, Y. Li, and G. Nie, “Multifunctional Biomolecule Nanostructures for Cancer Therapy,” Nature Reviews Materials 6 (2021): 766-783.

[244] Y. Dong, C. Yao, Y. Zhu, L. Yang, D. Luo, and D. Yang, “DNA Functional Materials Assembled From Branched DNA: Design, Synthesis, and Applications,” Chemical Reviews 120 (2020): 9420.

[245] N. C. Seeman and H. F. Sleiman, “DNA Nanotechnology,” Nature Reviews Materials 3 (2017): 17068.

[246] P. W. Rothemund, “Folding DNA to Create Nanoscale Shapes and Patterns,” Nature 440 (2006): 297-302.

[247] Y. Ke, L. L. Ong, W. M. Shih, and P. Yin, “Three-Dimensional Structures Self-Assembled From DNA Bricks,” Science 338 (2012): 1177-1183.

[248] L. L. Ong, N. Hanikel, O. K. Yaghi, et al., “Programmable Self-Assembly of Three-Dimensional Nanostructures From 10,000 Unique Components,” Nature 552 (2017): 72-77.

[249] S. Liu, Q. Jiang, X. Zhao, et al., “A DNA Nanodevice-Based Vaccine for Cancer Immunotherapy,” Nature Materials 20 (2021): 421-430.

[250] Y. Li and J. A. Champion, “Self-Assembling Nanocarriers From Engineered Proteins: Design, Functionalization, and Application for Drug Delivery,” Advanced Drug Delivery Reviews 189 (2022): 114462.

[251] P. V. Candelaria, L. S. Leoh, M. L. Penichet, and T. R. Daniels-Wells, “Antibodies Targeting the Transferrin Receptor 1 (TfR1) as Direct Anti-Cancer Agents,” Frontiers in Immunology 12 (2021): 607692.

[252] E. J. Lee, S. J. Lee, Y.-S. Kang, et al., “Engineered Proteinticles for Targeted Delivery of siRNA to Cancer Cells,” Advanced Functional Materials 25 (2015): 1279-1286.

[253] B. Zhang, X. Chen, G. Tang, et al., “Piezoelectric Enhanced Peroxidase-Like Activity of Metal-Free Sulfur Doped Graphdiyne Nanosheets for Efficient Water Pollutant Degradation and Bacterial Disinfection,” Nano Today 43 (2022): 101429.

[254] R. Wang, X. Zhang, K. Feng, et al., “Nanotechnologies Meeting Natural Sources: Engineered Lipoproteins for Precise Brain Disease Theranostics,” Asian Journal of Pharmaceutical Sciences 18 (2023): 100857.

[255] S. EL Andaloussi, I. Mäger, X. O. Breakefield, and M. J. Wood, “Extracellular Vesicles: Biology and Emerging Therapeutic Opportunities,” Nature Reviews Drug Discovery 12 (2013): 347-357.

[256] Y. Wang, H. Xie, Y. Wu, et al., “Bioinspired Lipoproteins of Furoxans-Oxaliplatin Remodel Physical Barriers in Tumor to Potentiate T-Cell Infiltration,” Advanced Materials 34 (2022): e2110614.

[257] T. Tan, H. Hu, H. Wang, et al., “Bioinspired Lipoproteins-Mediated Photothermia Remodels Tumor Stroma to Improve Cancer Cell Accessibility of Second Nanoparticles,” Nature Communications 10 (2019): 3322.

[258] R. H. Fang, W. Gao, and L. Zhang, “Targeting Drugs to Tumours Using Cell Membrane-Coated Nanoparticles,” Nature Reviews Clinical Oncology 20 (2023): 33-48.

[259] N. Krishnan, Y. Jiang, J. Zhou, et al., “A Modular Approach to Enhancing Cell Membrane-Coated Nanoparticle Functionality Using Genetic Engineering,” Nature Nanotechnology 19 (2024): 345-353.

[260] Z. Wu, Y. Chen, D. Mukasa, O. S. Pak, and W. Gao, “Medical Micro/Nanorobots in Complex Media,” Chemical Society Reviews 49 (2020): 8088-8112.

[261] B. J. Nelson and S. Pané, “Delivering Drugs with Microrobots,” Science 382 (2023): 1120-1122.

[262] T. Li, S. Yu, B. Sun, et al., “Bioinspired Claw-Engaged and Biolubricated Swimming Microrobots Creating Active Retention in Blood Vessels,” Science Advances 9 (2023): eadg4501.

[263] N. Arulkumaran, M. Singer, S. Howorka, and J. R. Burns, “Creating Complex Protocells and Prototissues Using Simple DNA Building Blocks,” Nature Communications 14 (2023): 1314.

[264] C. Zhang, L. Zhang, W. Wu, et al., “Artificial Super Neutrophils for Inflammation Targeting and HClO Generation against Tumors and Infections,” Advanced Materials 31 (2019): e1901179.

[265] S. Cheng, C. Xu, Y. Jin, et al., “Artificial Mini Dendritic Cells Boost T Cell-Based Immunotherapy for Ovarian Cancer,” Advanced Science 7 (2020): 1903301.

[266] Y. Jiang, N. Krishnan, J. Zhou, et al., “Engineered Cell-Membrane-Coated Nanoparticles Directly Present Tumor Antigens to Promote Anticancer Immunity,” Advanced Materials 32 (2020): e2001808.

[267] Y. Wang and T. M. Swi Chang, “Biodegradable Nanocapsules Containing a Nanobiotechnological Complex for the In-vitro Suppression of a Melanoma Cell Line B16F10,” Journal of Nanosciences: Current Research 01 (2016): 1000102.

[268] D. Machover, L. Rossi, J. Hamelin, et al., “Effects in Cancer Cells of the Recombinant L-Methionine Gamma-Lyase From Brevibacterium Aurantiacum. Encapsulation in Human Erythrocytes for Sustained L-Methionine Elimination,” Journal of Pharmacology and Experimental Therapeutics 369 (2019): 489-502.

[269] F. Yaman, A. Adler, and J. Beal, “AI Challenges in Synthetic Biology Engineering.” AAAI'18/IAAI'18/EAAI'18 AAAI Press, Article 972 (2018): 7884-7885.

[270] A. C. Komor, Y. B. Kim, M. S. Packer, J. A. Zuris, and D. R. Liu, “Programmable Editing of a Target Base in Genomic DNA without Double-Stranded DNA Cleavage,” Nature 533 (2016): 420-424.

[271] B. Y. Mok, M. H. de Moraes, J. Zeng, et al., “A Bacterial Cytidine Deaminase Toxin Enables CRISPR-Free Mitochondrial Base Editing,” Nature 583 (2020): 631-637.

[272] Z. Yang, X. Zeng, Y. Zhao, and R. Chen, “AlphaFold2 and Its Applications in the Fields of Biology and Medicine,” Signal Transduction and Targeted Therapy 8 (2023): 115.

[273] J. Huang, Q. Lin, H. Fei, et al., “Discovery of Deaminase Functions by Structure-Based Protein Clustering,” Cell 186 (2023): 3182-3195.

[274] T. Yuan, N. Yan, T. Fei, et al., “Optimization of C-to-G Base Editors with Sequence Context Preference Predictable by Machine Learning Methods,” Nature Communications 12 (2021): 4902.

[275] K. F. Marquart, A. Allam, S. Janjuha, et al., “Predicting Base Editing Outcomes with an Attention-Based Deep Learning Algorithm Trained on High-Throughput Target Library Screens,” Nature Communications 12 (2021): 5114.

[276] H. K. Kim, S. Min, M. Song, et al., “Deep Learning Improves Prediction of CRISPR-Cpf1 Guide RNA Activity,” Nature Biotechnology 36 (2018): 239-241.

[277] Q. Chen, G. Chuai, H. Zhang, et al., “Genome-Wide CRISPR off-Target Prediction and Optimization Using RNA-DNA Interaction Fingerprints,” Nature Communications 14 (2023): 7521.

[278] P. Patra, B. Disha, P. Kundu, M. Das, and A. Ghosh, “Recent Advances in Machine Learning Applications in Metabolic Engineering,” Biotechnology Advances 62 (2022): 108069.

[279] Y. Wang, H. Wang, L. Wei, S. Li, L. Liu, and X. Wang, “Synthetic Promoter Design in Escherichia coli Based on a Deep Generative Network,” Nucleic Acids Research 48 (2020): 6403-6412.

[280] H. Deng, H. Yu, Y. Deng, et al., “Pathway Evolution through a Bottlenecking-Debottlenecking Strategy and Machine Learning-Aided Flux Balancing,” Advanced Science 11 (2024): e2306935.

[281] Y. Xia, X. Du, B. Liu, S. Guo, and Y.-X. Huo, “Species-Specific Design of Artificial Promoters by Transfer-Learning Based Generative Deep-Learning Model,” Nucleic Acids Research 52 (2024): 6145-6157.

[282] M. HamediRad, R. Chao, S. Weisberg, J. Lian, S. Sinha, and H. Zhao, “Towards a Fully Automated Algorithm Driven Platform for Biosystems Design,” Nature Communications 10 (2019): 5150.

[283] P. Kumar, P. A. Adamczyk, X. Zhang, et al., “Active and Machine Learning-Based Approaches to Rapidly Enhance Microbial Chemical Production,” Metabolic Engineering 67 (2021): 216-226.

[284] C. J. Vavricka, S. Takahashi, N. Watanabe, et al., “Machine Learning Discovery of Missing Links That Mediate Alternative Branches to Plant Alkaloids,” Nature Communications 13 (2022): 1405.

[285] S. P. Foy, K. Jacoby, D. A. Bota, et al., “Non-Viral Precision T Cell Receptor Replacement for Personalized Cell Therapy,” Nature 615 (2023): 687-696.

[286] J. Z. Williams, G. M. Allen, D. Shah, et al., “Precise T Cell Recognition Programs Designed by Transcriptionally Linking Multiple Receptors,” Science 370 (2020): 1099-1104.

[287] C. Zhang, H. Liu, X. Li, F. Xu, and Z. Li, “Modularized Synthetic Biology Enabled Intelligent Biosensors,” Trends in Biotechnology 41 (2023): 1055-1065.

[288] D. C. Fajgenbaum and C. H. June, “Cytokine Storm,” New England Journal of Medicine 383 (2020): 2255-2273.

[289] X. Li, N. Gong, F. Tian, S. Zhang, et al., “Suppression of Cytokine Release Syndrome During CAR-T-Cell Therapy via a Subcutaneously Injected Interleukin-6-Adsorbing Hydrogel,” Nature Biomedical Engineering 7 (2023): 1129-1141.

[290] N. Gong, X. Han, L. Xue, et al., “In Situ PEGylation of CAR T Cells Alleviates Cytokine Release Syndrome and Neurotoxicity,” Nature Materials 22 (2023): 1571-1580.

[291] E. R. S. Cliff, A. H. Kelkar, D. A. Russler-Germain, et al., “High Cost of Chimeric Antigen Receptor T-Cells: Challenges and Solutions,” American Society of Clinical Oncology Educational Book 2023, e397912.

[292] C. Roddie, M. O'Reilly, J. Dias Alves Pinto, K. Vispute, and M. Lowdell, “Manufacturing Chimeric Antigen Receptor T Cells: Issues and Challenges,” Cytotherapy 21 (2019): 327-340.

[293] S. Pandit, P. Agarwalla, F. Song, A. Jansson, G. Dotti, and Y. Brudno, “Implantable CAR T Cell Factories Enhance Solid Tumor Treatment,” Biomaterials 308 (2024): 122580.

[294] S. Jo, S. Das, A. Williams, A. S. Chretien, et al., “Endowing Universal CAR T-Cell with Immune-Evasive Properties Using TALEN-Gene Editing,” Nature Communications 13 (2022): 3453.

[295] Y.-R. Li, Y. Zhou, J. Yu, et al., “Generation of Allogeneic CAR-NKT Cells from Hematopoietic Stem and Progenitor Cells using a Clinically Guided Culture Method,” Nature Biotechnology (2024).

[296] Y. Hu, Y. Zhou, M. Zhang, et al., “Genetically Modified CD7-Targeting Allogeneic CAR-T Cell Therapy with Enhanced Efficacy for Relapsed/Refractory CD7-Positive Hematological Malignancies: A Phase I Clinical Study,” Cell Research 32 (2022): 995-1007.

[297] S. Badrinath, M. O. Dellacherie, A. Li, et al., “A Vaccine Targeting Resistant Tumours by Dual T Cell plus NK Cell Attack,” Nature 606 (2022): 992-998.

[298] M. J. Dickinson, P. Barba, U. Jäger, et al., “A Novel Autologous CAR-T Therapy, YTB323, With Preserved T-Cell Stemness Shows Enhanced CAR T-Cell Efficacy in Preclinical and Early Clinical Development,” Cancer Discovery 13 (2023): 1982-1997.

[299] N. Francis, M. Braun, S. Neagle, et al., Molecular Therapy—Methods & Clinical Development 31 (2023): 101114.

[300] J. Bailey, “CRISPR-Mediated Gene Editing: Scientific and Ethical Issues,” Trends in Biotechnology 37 (2019): 920-921.

[301] N. Kofler, “Why Were Scientists Silent over Gene-Edited Babies?,” Nature 566 (2019): 427.

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