Genetically Encoded Synthetic Beta Cells for Insulin Biosynthesis and Release under Hyperglycemic Conditions

Abstract

Advances in artificial/synthetic cells have drawn a new era of nanobiotechnology, which have shown broad prospects in biomedical applications. The rational nanoengineering of synthetic cells that can closely substitute the systematic biological functions of cells is a next grand challenge. Here, a genetically encoded synthetic beta cell, which can sense hyperglycemic conditions to initiate programmed biosynthesis and secretion of insulin is reported. By encapsulating different metal–organic framework‐based artificial organelles with distinctive bifunctionalities, the synthetic cell can undergo programmed, sequential subcellular events, including glucose sensing, initiation of insulin gene transcription and translation, and finally excretion of functional insulin, under hyperglycemic conditions. Glucose uptake assay suggests that the insulin produced by the synthetic cells can successfully promote glucose uptake into mammalian cells. The construction of a higher‐order cell cluster by ligand‐mediated super‐assembly of the synthetic cells is further demonstrated. Such a robust and smart synthetic system that closely mimics the cellular activities of beta cells in response to glucose levels is promising for improving clinical outcomes in diabetes treatment.

Artificial Cells: Past, Present and Future

“…Liu et al reported a MOF-based artificial β cell; the encapsulated MOF organelles sense hyperglycemia in the environment, start programmed insulin gene transcription and protein translation and then secrete insulin. 84 The structure of the natural cell membrane can be dynamically modified by enzyme remodeling of acyl chains and polar heads to regulate signal transduction or binding.…”

“…24 Recently, Liu et al reported a genetically encoded artificial neural network β cell that senses hyperglycemia in the environment and synthesizes and secretes insulin to promote glucose uptake by mammalian cells. 84 Liu et al synthesized artificial cells with high blood compatibility and a long blood circulation time using erythrocyte membrane fragments containing hemoglobin and prefabricated polysaccharide polynucleotide aggregates containing GOx. 81 In the presence of glucose and hydroxyurea, this artificial cell continuously produces nitric oxide (NO), sends signals to vascular cells and induces vasodilation.…”

“…After the template is removed, the complex of capsule structure is obtained to construct artificial cells (Figure B) . The specific membrane permeability of MPN gives artificial cells composed of MPN the possibility of uptake of molecules and excreting substances; furthermore, the physical and chemical properties of MOF organelles encapsulated by MPN are more stable and maintain biological activity after ultraviolet and heat treatment …”

“…Additionally, the feedback pathway inside the artificial cell switches the nanogatekeeper back to the closed state after the cell responds. Liu et al reported a MOF-based artificial β cell; the encapsulated MOF organelles sense hyperglycemia in the environment, start programmed insulin gene transcription and protein translation and then secrete insulin …”

Enzymes-Encapsulated Defective Metal–Organic Framework Hydrogel Coupling with a Smartphone for a Portable Glucose Biosensor

“…To this point, zeolite imidazole frameworks (ZIFs), including ZIF-8, ZIF-90, MAF-7, and so forth, are the favorable MOF matrices for enzyme immobilization due to their biocompatible synthesis conditions. − A pioneering work by Liang, Falcaro, and co-workers has found that ZIF-8 could in situ crystallize around a given enzyme, analogous to the natural biomineralization . Utilizing this method, single or multiple enzymes are readily encapsulated into ZIFs, and the encapsulated enzymes display improved stability yet maintain desirable bioactivity. − However, these ZIFs biohybrids are microcrystalline powders and hence are difficult to be mechanically processed and shaped in a controllable manner. This significantly limits the MOF biohybrid acting as the core element in large-scale industrial applications, such as portable biosensors.…”