Leveraging Engineering of Cells for Drug Delivery.

Cell therapy has become a momentum-gathering treatment strategy for a variety of diseases, including cancer, diabetes, hemophilia, and cardiomyopathy. However, clinical applications of conventional cell therapies have often been compromised by rapid decline in viability and function of the transplanted cells due to host recognition and subsequent foreign body rejection. Along this line, cell engineering technologies such as cell encapsulation within microcapsules and immobilization in porous scaffolds have been implemented to address the immunosuppression concerns. As a recent emerging research topic, drawing inspiration from the ways that natural cells interact with the body has opened new avenues for cell engineering, such as direct modification of whole cells with synthetic materials and "top-down" integration of biological membranes with micro/nanomaterials, which aim to alleviate immune response while harnessing the complex biological functions of cells. In this Account, we summarize our recent contribution to the field of cell engineering methodologies, with which we have demonstrated their promising applications for cancer immunotherapy, targeted drug delivery, and blood glucose regulation. For example, inspired by the inherent ability of platelets to accumulate at wound sites and interact with circulating tumor cells, we exploited a targeted checkpoint antibody delivery strategy for treatment of postsurgical cancer recurrence and metastatic spread by covalent binding of platelets' cell surfaces with a monoclonal antibody against programmed-death ligand 1 (aPDL1). Without interfering with the platelets' surgical-site homing property, the conjugated aPDL1 could be triggered to release in the form of microparticles after in situ activation. As an extension, we then engineered the platelet membrane to cloak nanoparticles for anticancer drug delivery, mimicking the targeting capability of the source cells while possessing prolonged circulation lifetime and insignificant immunogenicity. At the same time, we also found that the subcellular compartment membrane-derived particulates exhibited high specificity toward homotypic cells, by which enhanced intracellular drug delivery was achieved. Moreover, by taking advantage of the reversible interaction between glucose-derivative-modified insulin and the red blood cell membrane, we constructed a glucose-responsive smart insulin delivery system for long-term maintenance of blood glucose levels within a normal range. Recently, by virtue of painless microneedle patches as convenient cell engineering platforms, a minimally invasive intradermal antitumor vaccine was invented by integrating whole-tumor lysis into near-infrared light-illuminated microneedle patches. The microneedle patches also showed promise in combining with conventional cell encapsulation techniques, by which an externally positioned β-cell engineering strategy was proposed for diabetes treatment. The results presented in this Account demonstrate distinct approaches to the development and application of cell engineering strategies for drug delivery.