A Bioinspired Manganese-Organic Framework Ameliorates Ischemic Stroke through its Intrinsic Nanozyme Activity and Upregulating Endogenous Antioxidant Enzymes.

Following stroke, oxidative stress induced by reactive oxygen species (ROS) aggravates neuronal damage and enlarges ischemic penumbra, which is devastating to stroke patients. Nanozyme-based antioxidants are emerging to treat stroke through scavenging excessive ROS. However, most of nanozymes cannot efficiently scavenge ROS in neuronal cytosol and mitochondria, due to low-uptake abilities of neurons and barriers of organelle membranes, significantly limiting nanozymes' neuroprotective effects. To overcome this limitation, a manganese-organic framework modified with polydopamine (pDA-MNOF), capable of not only mimicking catalytic activities of natural SOD2's catalytic domain but also upregulating two endogenous antioxidant enzymes in neurons is fabricated. With such a dual anti-ROS effect, this nanozyme robustly decreases cellular ROS and effectively protects them from ROS-induced injury. STAT-3 signaling is found to play a vital role in pDA-MNOF activating the two antioxidant enzymes, HO1 and SOD2. In vivo pDA-MNOF treatment significantly improves the survival of middle cerebral artery occlusion (MCAo) mice by reducing infarct volume and more importantly, promotes animal behavioral recovery. Further, pDA-MNOF activates vascular endothelial growth factor expression, a downstream target of STAT3 signaling, thus enhancing angiogenesis. Taken together, the biochemical, cell-biological, and animal-level behavioral data demonstrate the potentiality of pDA-MNOF as a dual ROS-scavenging agent for stroke treatment.

Identification of Aging and Young Subtypes for Predicting Colorectal Cancer Prognosis and Immunotherapy Responses.

Colorectal cancer (CRC) is critically related to aging and severely threatens human lives. To better explore the effects of aging on CRC progression and therapy outcome, a reliable aging subtypes identification of CRC is urgently desired. Here, 28 aging-related genes associated with the CRC prognosis were selected by univariate Cox analyses. Based on these 28 genes, CRC patients were divided into the aging subtype and young subtype by non-negative matrix factorization clustering. Aging subtype and young subtype of CRC were identified with distinct molecular features and clinical prognosis. The aging subtype was characterized by upregulation of senescence-associated secretory phenotype, higher frequencies of TP53 and immune checkpoint molecules, and high sensitivity to protein kinase and angiogenesis inhibitors. Furthermore, 14 genes were selected by LASSO penalized Cox regression analyses for aging-related risk signature construction. The constructed aging risk signature exhibited good prediction and the nomogram showed robust discrimination power over the traditional CRC staging system. In conclusion, this study successfully established aging subtype and young subtype of CRC, which is helpful to identify patients with aging characteristics to evaluate prognosis and treatment outcomes. Introducing aging-based subtypes into clinical concern and patient prognostication provides new opportunities for personalized CRC treatment.

Oxygen-Generating Cyanobacteria Powered by Upconversion-Nanoparticles-Converted Near-Infrared Light for Ischemic Stroke Treatment.

Stroke is one of most common causes of death and disability. Most of neuroprotective agents fail to rescue neurons from cerebral ischemic insults, mainly because of targeting downstream cascading events, such as excitotoxicity, oxidative and nitrosative stress, and inflammation, rather than improving hypoxia that initially occurs. Here, we report a near-infrared light (NIR)-driven nanophotosynthesis biosystem capable of generating oxygen and absorbing carbon dioxide, thus rescuing neurons from ischemia toward treating stroke. Through cerebral delivery of S. elongatus that spontaneously photosynthesize and upconversion nanoparticles (UCNPs), NIR with excellent tissue penetrating capability is converted to visible light by UCNPs to activate S. elongatus generating oxygen in vivo, enhancing angiogenesis, reducing infarction, and facilitating repair of brain tissues, thus improving neuronal function recovery. The combination of cell-biological, biochemical, and animal-level behavioral data provides compelling evidence demonstrating that this oxygen-generating biosystem through jointly utilizing microorganism and nanotechnology represents a novel approach to stroke treatment.

Injectable silk sericin scaffolds with programmable shape-memory property and neuro-differentiation-promoting activity for individualized brain repair of severe ischemic stroke.

Severe ischemic stroke damages neuronal tissue, forming irregular-shaped stroke cavities devoid of supporting structure. Implanting biomaterials to provide structural and functional support is thought to favor ingrowth of regenerated neuronal networks. Injectable hydrogels capable of in situ gelation are often utilized for stroke repair, but challenged by incomplete gelation and imprecise control over end-macrostructure. Injectable shape-memory scaffolds might overcome these limitations, but are not explored for stroke repair. Here, we report an injectable, photoluminescent, carbon-nanotubes-doped sericin scaffold (CNTs-SS) with programmable shape-memory property. By adjusting CNTs' concentrations, CNTs-SS' recovery dynamics can be mathematically calculated at the scale of seconds, and its shapes can be pre-designed to precisely match any irregular-shaped cavities. Using a preclinical stroke model, we show that CNTs-SS with the customized shape is successfully injected into the cavity and recovers its pre-designed shape to well fit the cavity. Notably, CNTs-SS' near-infrared photoluminescence enables non-invasive, real-time tracking after in vivo implantation. Moreover, as a cell carrier, CNTs-SS not only deliver bone marrow mesenchymal stem cells (BMSCs) into brain tissues, but also functionally promote their neuronal differentiation. Together, we for the first time demonstrate the feasibility of applying injectable shape-memory scaffolds for stroke repair, paving the way for personalized stroke repair.