Immuno-engineering is an emerging field of research with many opportunities to deliver and present biomolecules to program diverse populations of lymphocytes to fight disease. Based on the improved understanding of the molecular and physical mechanics of lymphocyte activation, as well as the increasingly evolving technology, varied strategies for engineering surfaces to activate and deactivate T-Cells, B-Cells and natural killer (NK) cells are in preclinical and clinical development. Lymphocyte surface engineering has been a very promising approach in developing novel lymphocyte-based therapeutics.
Originated from stem cells in the bone marrow and primarily exist in the blood and lymphoid tissues, lymphocytes include T-Cells, B-Cells and NK cells, both of which offer great promise in the fight against infections and cancers. Especially, T cells and B cells play important roles in protective activities and immune response, such as antigen detection, pathogen clearance, disease site infiltration, and abnormal cell destruction. Therefore, lymphocytes have become promising candidates for cancer immunotherapy and drug delivery.
Genetically engineering lymphocytes is a robust modification technique, but has a number of significant drawbacks, such as complicated procedures and potential toxicities. Surface engineering of lymphocytes has emerged as a powerful and compatible complement to trigger an enhanced immune reaction and improve cell-based therapeutics.
Stephan et al. developed an alternate strategy to enhance cell therapy via the conjugation of adjuvant drug-loaded nanoparticles to the surfaces of therapeutic donor cells (adoptive T cells). They chemically conjugated cytokines-carrier synthetic nanoparticles to the surface of therapeutic cells via maleimide thiol coupling, enabling continuous pseudoautocrine stimulation of their cellular carriers in vivo. These surface engineered T cells efficiently targeted surface-tethered nanoparticles into antigen-expressing tumors, markedly amplified the proliferation of their cellular carriers, and significantly prevented tumor growth 30 d after T cell treatment.
Fig.1 Schematic of maleimide-based conjugation to cell surface thiols. (Stephan, 2010)
Huang et al. recently reported a promising study of T cell surface engineering for active targeting drug delivery. They used lymphocytes as “Trojan horses” to deliver SN-38-loaded lipid nanoparticles via a maleimide-thiol reaction to address the challenge of poor pharmacokinetics of SN-38. They revealed that this loading mediated the efficient killing of lymphoma cells without causing acute toxicity to the carrier cell. SN-38-loaded lipid nanoparticles markedly suppressed tumor growth, exhibiting a significant reduction (60-fold smaller) in tumor burden relative to the free drug or untreated animals.
Fig.2 Schematic of T cell functionalization and cell-mediated delivery of SN-38 NCs into tumors. (Huang, 2015)
Liu et al. developed a novel pH-sensitive bond to chemically modify the self-immolative chemotherapeutics-albumin complex onto the surface of T lymphocytes to enhance tumor penetration and antitumor efficacy. Dexterously, they decorated the redox responsive doxorubicin-albumin conjugates (DOX-A) onto the surface of T lymphocytes via a pH-sensitive bond, which allows for the responsive release of DOX-A within the weak acid tumor microenvironment, however, DOX-A on the surface of T lymphocytes maintained stable retention in blood circulation. The released DOX-A showed deep tumor penetration, efficient tumor cell uptake and rapid intracellular drug release via redox responsive cleavage.
Fig.3 DOX-A@T cells potentiates immune response in tumor microenvironment. (Liu, 2019)
Engineering lymphocytes’ surface with natural ligands, functional biological components, or synthetic materials is a unique and powerful strategy to modulate cell function. It is also a promising strategy to enhance cell therapy via the conjugation of adjuvant drug-loaded nanoparticles to the surfaces of therapeutic lymphocytes. Based on leading-edge facilities and profound knowledge, Creative Biolabs has made many endeavors to develop lymphocyte surface engineering techniques to endow lymphocytes with new functions to enhance drug delivery efficiency and immunotherapy effects. Please contact us for more detailed information to know how we can help.
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