Extracellular matrices of living tissues exhibit viscoelastic properties, yet how these properties regulate chromatin and the epigenome remains unclear. Here, we show that viscoelastic substrates induce changes in nuclear architecture and epigenome, with more pronounced effects on softer surfaces. Fibroblasts on viscoelastic substrates display larger nuclei, lower chromatin compaction, and differential expression of distinct sets of genes related to the cytoskeleton and nuclear function, compared to those on elastic surfaces. Slow-relaxing viscoelastic substrates reduce lamin A/C expression and enhance nuclear remodeling. These structural changes are accompanied by a global increase in euchromatin marks and local increase in chromatin accessibility at cis-regulatory elements associated with neuronal and pluripotent genes. Consequently, viscoelastic substrates improve the reprogramming efficiency from fibroblasts into neurons and induced pluripotent stem cells. Collectively, our findings unravel the roles of matrix viscoelasticity in epigenetic regulation and cell reprogramming, with implications for designing smart materials for cell fate engineering.

Tumor-associated adipocytes (TAAs) recruit monocytes and promote their differentiation into tumor-associated macrophages (TAMs) that support tumor development. Here, TAAs are engineered to promote the polarization of TAMs to the tumor suppressive M1 phenotype. Telratolimod, a toll-like receptor 7/8 agonist, is loaded into the lipid droplets of adipocytes to be released at the tumor site upon tumor cell-triggered lipolysis. Locally administered drug-loaded adipocytes increased tumor suppressive M1 macrophages in both primary and distant tumors and suppressed tumor growth in a melanoma model. Furthermore, drug-loaded adipocytes improved CD8+ T cell-mediated immune responses within the tumor microenvironment and favored dendritic cell maturation in the tumor draining lymph nodes.

Glucose-responsive insulin delivery systems that mimic insulin secretion activity in the pancreas show great potential to improve clinical therapeutic outcomes for people with type 1 and advanced type 2 diabetes. Here, we report a glucose-responsive insulin delivery microneedle (MN) array patch that is loaded with red blood cell (RBC) vesicles or liposome nanoparticles containing glucose transporters (GLUTs) bound with glucosamine-modified insulin (Glu-Insulin). In hyperglycemic conditions, high concentrations of glucose in interstitial fluid can replace Glu-Insulin via a competitive interaction with GLUT, leading to a quick release of Glu-Insulin and subsequent regulation of blood glucose (BG) levels in vivo. To prolong the effective glucose-responsive insulin release from MNs, additional free Glu-Insulin, which serves as "stored insulin", is loaded after RBC vesicles or liposome nanoparticles bound with Glu-Insulin. In the streptozotocin (STZ)-induced type 1 diabetic mouse model, this smart GLUT-based insulin patch can effectively control BG levels without causing hypoglycemia.

A microdevice that offers glucagon supplements in a safe, non-invasive, and glucose-responsive manner is ideal for avoiding fatal hypoglycemia consequences from insulin overdosage during daily diabetes treatment. However, mold-assisted microfabrication of biomedical materials or devices typically needs high-resolution laser ablation to scale down structural design. In addition, the majority of the polymeric drug delivery materials being used to fabricate devices are dissolvable or deformable in aqueous environments, which restricts washing-based cleaning and purification procedures post shape fixation. This study leverages the design flexibility of 3D printing-assisted mold casting and presents a shrinking microfabrication approach that allows subsequent washing procedures to remove toxic monomer residues during polymerization. The feasibility of this approach is demonstrated by developing a glucose-responsive transdermal glucagon microneedle patch through matrix volume change-mediated release kinetic control. Shown in the type 1 diabetic mouse model, this transdermal patch can reverse the occurrence of hypoglycemia while lowering the risk of monomer residue-induced irritation during treatment. Freeing from the restrain of molding resolution for microstructure design, this shrinking methodology further provides an insight into post-fabrication purifications of biomedical materials.

In article number 2100629, Liping Jiang, Jun-Jie Zhu, Zhen Gu and co-workers develop a lipid-droplet-based drug delivery system for cancer photodynamic therapy. The lipid droplet, which is derived from adipocytes, is leveraged to potentiate the anticancer efficacy of the lipid-conjugated drug.

Engineering of efficient and safe materials remains a challenge for cancer therapy. Here, the lipid droplet, an organelle in adipocytes, is demonstrated to be a controllable and biocompatible vehicle to deliver anticancer drugs. It is validated that isolated lipid droplets maintain their key physiological functions to interact with other organelles and augment the therapeutic effect of cancer photodynamic therapy by encapsulation with a lipid-conjugated photosensitizer (Pyrolipid) through a variety of pathways, including generation of reactive oxygen species (ROS); lipid peroxidation; and endoplasmic reticulum (ER) stress. As such, the IC50 value of Pyrolipid is reduced by 6.0-fold when loaded into the lipid droplet. Of note, in vivo results demonstrate that engineered lipid droplets induce significant inhibition of tumor growth with minimal side effects.

Exercise interventions alter the DNA methylation profile in skeletal muscle, yet little is known about the role of the DNA methylation machinery in exercise capacity. In this study, we found that in oxidative red muscle, DNMT3A expression increases greatly following a bout of endurance exercise. Mice lacking in skeletal muscle fibers had reduced tolerance to endurance exercise, accompanied by reduced oxidative capacity and reduced mitochondrial counts. Moreover, during exercise, the knockout muscles overproduced reactive oxygen species (ROS), which are major contributors to muscle dysfunction. In mechanistic terms, we demonstrated that is a key target of repression by DNMT3A in red muscles. DNMT3A directly regulated the Aldh1l1 transcription by binding to the promoter region and altering DNA methylation and histone modification. Enforcing ALDH1L1 expression, leading to elevated NADPH, led to overproduction of ROS by the NADPH oxidase complex (NOX) in myotubes, ultimately resulting in mitochondrial defects. Moreover, both genetic inhibition of ALDH1L1 and pharmacological inhibition of NOX rescued oxidative stress and mitochondrial decline in -deficient myotubes, confirming the essential role of ALDH1L1-dependent ROS generation as a downstream effector of DNMT3A loss of function. Together, our results reveal that DNMT3A in skeletal muscle plays a pivotal role in endurance exercise by controlling intracellular oxidative stress.

It has been suggested that beige fat thermogenesis is tightly controlled by epigenetic regulators that sense environmental cues such as temperature. Here, we report that subcutaneous adipose expression of the DNA demethylase TET1 is suppressed by cold and other stimulators of beige adipocyte thermogenesis. TET1 acts as an autonomous repressor of key thermogenic genes, including Ucp1 and Ppargc1a, in beige adipocytes. Adipose-selective Tet1 knockout mice generated by using Fabp4-Cre improves cold tolerance and increases energy expenditure and protects against diet-induced obesity and insulin resistance. Moreover, the suppressive role of TET1 in the thermogenic gene regulation of beige adipocytes is largely DNA demethylase-independent. Rather, TET1 coordinates with HDAC1 to mediate the epigenetic changes to suppress thermogenic gene transcription. Taken together, TET1 is a potent beige-selective epigenetic breaker of the thermogenic gene program. Our findings may lead to a therapeutic strategy to increase energy expenditure in obesity and related metabolic disorders.

Obesity is a complex disease attributable to many factors including genetics and environmental influences. Growing evidence suggests that gut microbiota is a major contributing factor to the pathogenesis of obesity and other metabolic disorders. This article reviews the current understanding of the role of gut microbiota in the regulation of energy balance and the development of obesity, and how the microbiota communicates with host tissues, in particular adipose tissue. We discuss several external factors that interfere with the interplay between gut microbiota and host tissue metabolism, including cold exposure, diet regimens, and genetic manipulations. We also review the role of diet-derived metabolites that regulate thermogenesis and thus energy homeostasis. Among the gut microbial metabolites, we emphasize short-chain fatty acids, which could be utilized by the host as a direct energy source while regulating the appetite of the host through the gut-brain axis.

The two types of thermogenic fat cells, beige and brown adipocytes, play a significant role in regulating energy homeostasis. Their development and thermogenesis are tightly regulated by dynamic epigenetic mechanisms, which could potentially be targeted to treat metabolic disorders such as obesity. However, we are just beginning to catalog and understand these dynamic changes. In this review, we will discuss the current understanding of the role of DNA (de)methylation events in beige and brown adipose biology in order to highlight the holes in our knowledge and to point the way forward for future studies.