Nanocoating of a single-cell with biocompatible materials creates a defined microenvironment for cell differentiation and proliferation, as well as a model for studies in cell biology. In addition, the acidic environment in the tissue of stroke victims necessitates drug release upon pH stimuli. Here, we report the encapsulation of single neural stem cells (NSCs) using a layer-by-layer (LbL) self-assembly technique with polyelectrolytes gelatin and alginate. Analysis of the NSCs showed that the LbL encapsulation would not affect the viability, proliferation, or differentiation of the cells. When insulin-like growth factor-1 (IGF-1) was loaded on the coating material alginate, its release from alginate into the medium presented in a time-dependent and pH-dependent way. IGF-1 significantly enhanced the proliferation of the encapsulated NSCs, demonstrating a drug-carrier function of the LbL single-cell nanocoating. It provided a potential treatment strategy for nervous system disorders such as stroke.

The encapsulation of cells with various polyelectrolytes through layer-by-layer (LbL) has become a popular strategy in cellular function engineering. The technique sprang up in 1990s and obtained tremendous advances in multi-functionalized encapsulation of cells in recent years. This review comprehensively summarized the basis and applications in drug delivery by means of LbL cell encapsulation. To begin with, the concept and brief history of LbL and LbL cell encapsulation were introduced. Next, diverse types of materials, including naturally extracted and chemically synthesized, were exhibited, followed by a complicated basis of LbL assembly, such as interactions within multilayers, charge distribution, and films morphology. Furthermore, the review focused on the protective effects against adverse factors, and bioactive payloads incorporation could be realized via LbL cell encapsulation. Additionally, the payload delivery from cell encapsulation system could be adjusted by environment, redox, biological processes, and functional linkers to release payloads in controlled manners. In short, drug delivery via LbL cell encapsulation, which takes advantage of both cell grafts and drug activities, will be of great importance in basic research of cell science and biotherapy for various diseases.

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Intracerebral hemorrhage (ICH) poses a great threat to human health because of its high mortality and morbidity. Neural stem cell (NSC) transplantation is promising for treating white matter injury following ICH to promote functional recovery. However, reactive oxygen species (ROS)‐induced NSC apoptosis and uncontrolled differentiation hindered the effectiveness of the therapy. Herein, we developed a single‐cell nanogel system by layer‐by‐layer (LbL) hydrogen bonding of gelatin and tannic acid (TA), which was modified with a boronic ester‐based compound linking triiodothyronine (T3). In vitro, NSCs in nanogel were protected from ROS‐induced apoptosis, with apoptotic signaling pathways downregulated. This process of ROS elimination by material shell synergistically triggered T3 release to induce NSC differentiation into oligodendrocytes. Furthermore, in animal studies, ICH mice receiving nanogels performed better in behavioral evaluation, neurological scaling, and open field tests. These animals exhibited enhanced differentiation of NSCs into oligodendrocytes and promoted white matter tract regeneration on Day 21 through activation of the αvβ3/PI3K/THRA pathway. Consequently, transplantation of LbL(T3) nanogels largely resolved two obstacles in NSC therapy synergistically: low survival and uncontrolled differentiation, enhancing white matter regeneration and behavioral performance of ICH mice. As expected, nanoencapsulation with synergistic effects would efficiently provide hosts with various biological benefits and minimize the difficulty in material fabrication, inspiring next‐generation material design for tackling complicated pathological conditions.