Therapeutic Cell Engineering with Surface-Conjugated Synthetic Nanoparticles

In the field of cancer immunotherapy, cell therapy has yielded promising results and provided great help. However, a major limitation arises after cell transfer, therapeutic cells usually rely on the simultaneous delivery of adjuvant drugs to maximize donor cell efficacy and in vivo persistence to achieve therapeutic effects. The results lead to in dose-limiting toxicity of the drugs due to their generally pleiotropic activity, thus restricting their clinical use. A team from Massachusetts Institute of Technology (MIT) has described a strategy to enhance cell therapy via the conjugation of adjuvant drug-loaded nanoparticles to the surfaces of therapeutic cells by providing sustained pseudoautocrine stimulation to donor cells.

In a series of experiments, a significant enhancement of tumor elimination was found in a model of adoptive T cell therapy for cancer and also increased in vivo reproliferation rates of hematopoietic stem cell transplantation using very low doses of adjuvant drugs that were ineffective when given systemically.

The experimental procedures and results are as follows:

1. According to previous reports confirmed the detection of large amounts of free thiols on the surface of T cells, B cells, and HSCs, through which synthetic drug carriers are connected to the cells, using 100-300nm nanoparticles in diameter synthesized by liposomes and liposome-like, in which the lipid bilayer surface of the particles included thiol-reactive maleimide headgroups. This approach demonstrates that from simple liposomes (with an aqueous drug-loaded core) to more complex multi­lamellar lipid nanoparticles or lipid-coated polymer nanoparticles are stably attached to living cells and ~300-nm multilamellar lipid nanoparticles were selected for subsequent in vitro function and in vivo therapeutic studies.

2. Research has shown that connecting to cells based on the determination of the maximum number of particles (no encapsulated drug cargo) does not compromise key cellular functions, focusing on therapeutic cytotoxicity T cells confirmed from three aspects, these cells must be able to form immune synapses and kill target cells, and proliferate and secrete cytokines as part of their normal function. A first aspect is that, during cell division, nanoparticles attached to the surface are equally segregated to daughter cells and have no effect on T cell recognition or killing of ovalbumin peptide pulse target cells or cytokine release profiles. The second aspect assessed the impact of cell surface–tethered nanoparticles on T cell transmigration across endothelial monolayers and showed that the migration efficiency of T cells carrying nanoparticles per cell was not altered. The third aspect determined that in vivo tissue homing of T cells was not affected by nanoparticle conjugation by evaluating the tumor-homing properties of particle-conjugated lymphocytes.

3. Using adoptively transferred melanoma-specific Pmel-1 CD8+ T cells17, the test of cell-bound adjuvant drug–loaded nanoparticles showed that the cell carrier could be directly assigned to amplify therapeutic function, demonstrating that targeted cytokines support anti-tumor T cells.

4.On the basis of whole-body photon emission from donor HSCs of transgenic firefly luciferase, the frequency of GFP+ donor HSCs was tracked by flow cytometry to assess the in vivo repopulation capabilities of hematopoietic grafts supported by cell-bound, TWS119-loaded nanoparticles. This suggests that the approach of modifying donor cells before cell transfer leads to enhance HSC transplants.

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