Traumatic brain injury (TBI) is recognized as a global health problem due to its increasing occurrence, challenging treatment, and persistent impacts on brain pathophysiology. Neural cell death in ...patients with TBI swiftly causes inflammation in the injured brain areas, which is recognized as focal brain inflammation. Focal brain inflammation causes secondary brain injury by exacerbating brain edema and neuronal death, while also exerting divergent beneficial effects, such as sealing the damaged limitans and removing cellular debris. Recent evidence from patients with TBI and studies on animal models suggest that brain inflammation after TBI is not only restricted to the focal lesion but also disseminates to remote areas of the brain. The dissemination of inflammation has been detected within days after the primary injury and persists chronically. This state of inflammation may be related to remote complications of TBI in patients, such as hyperthermia and hypopituitarism, and may lead to progressive neurodegeneration, such as chronic traumatic encephalopathy. Future studies should focus on understanding the mechanisms that govern the initiation and propagation of brain inflammation after TBI and its impacts on post-trauma brain pathology.
Controlled delivery of protein therapeutics remains a challenge. Here, the inclusion of diselenide‐bond‐containing organosilica moieties into the framework of silica to fabricate biodegradable ...mesoporous silica nanoparticles (MSNs) with oxidative and redox dual‐responsiveness is reported. These diselenide‐bridged MSNs can encapsulate cytotoxic RNase A into the 8–10 nm internal pores via electrostatic interaction and release the payload via a matrix‐degradation controlled mechanism upon exposure to oxidative or redox conditions. After surface cloaking with cancer‐cell‐derived membrane fragments, these bioinspired RNase A‐loaded MSNs exhibit homologous targeting and immune‐invasion characteristics inherited from the source cancer cells. The efficient in vitro and in vivo anti‐cancer performance, which includes increased blood circulation time and enhanced tumor accumulation along with low toxicity, suggests that these cell‐membrane‐coated, dual‐responsive degradable MSNs represent a promising platform for the delivery of bio‐macromolecules such as protein and nucleic acid therapeutics.
Diselenide‐bond‐containing organosilica moieties are introduced into the framework of mesoporous silica to fabricate biodegradable mesoporous silica nanoparticles (MSNs) with an oxidative and redox dual‐responsive degradable feature. After surface cloaking with cancer‐cell‐derived membrane fragments, these bioinspired RNase‐A‐loaded MSNs exhibit homologous targeting and immune escape abilities, leading to efficient in vitro and in vivo anti‐cancer performance along with low toxicity.
Chemotherapy causes off‐target toxicity and is often ineffective against solid tumors. Targeted and on‐demand release of chemotherapeutics remains a challenge. Here, cancer‐cell‐membrane‐coated ...mesoporous organosilica nanoparticles (MONs) containing X‐ray‐ and reactive oxygen species (ROS)‐responsive diselenide bonds for controlled release of doxorubicin (DOX) at tumor sites are developed. DOX‐loaded MONs coated with 4T1 breast cancer cell membranes (CM@MON@DOX) show greater accumulation at tumor sites and prolonged blood circulation time versus an uncoated control in mice bearing 4T1 orthotopic mammary tumors. Under low‐dose X‐ray radiation, the DOX‐loaded MONs exhibit carrier degradation‐controlled release via cleavage of diselenide bonds, resulting in DOX‐mediated immunogenic cell death at the tumor site. Combination with a PD‐L1 checkpoint blockade further enhances inhibition of tumor growth and metastasis with low systemic toxicity. Together, the findings show the promise of these biomimetic, radiation‐responsive diselenide‐bond‐bridged MONs in chemo‐immunotherapy.
Biomimetic mesoporous organosilica nanoparticles are tailored for radiation‐responsive delivery of doxorubicin to solid tumors and are combined with a PD‐L1 checkpoint blockade as a chemo‐immunotherapy strategy. Under low‐dose X‐ray radiation, these cancer‐cell‐membrane‐coated nanotherapeutics exhibit degradation‐controlled drug release and induce anti‐tumor immune responses, leading to enhanced tumor regression and metastasis inhibition with low systemic toxicity when combined with anti‐PD‐L1.
Traumatic brain injury (TBI) is a leading cause of death and disability. Patients with isolated TBI lose a limited amount of blood to primary injury, but they often develop secondary coagulopathy, ...resulting in delayed or recurrent intracranial and intracerebral hematoma. TBI‐induced coagulopathy is closely associated with poor outcomes for these patients, including death. This secondary coagulopathy is consumptive in nature, involving not only brain‐derived molecules, coagulation factors, and platelets, but also endothelial cells in a complex process now called blood failture. A key question is how a localized injury to the brain is rapidly disseminated to affect systemic hemostasis that is not directly affected the way it is in trauma to the body and limbs, especially with hemorrhagic shock. Increasing evidence suggests that the adhesive ligand von Willebrand factor (VWF), which is synthesized in and released from endothelial cells, plays a paradoxical role in both facilitating local hemostasis at the site of injury and also propagating TBI‐induced endotheliopathy and coagulopathy systemically. This review discusses recent progress in understanding these diverse activities of VWF and the knowledge gaps in defining their roles in TBI and associated coagulopathy.
Traumatic brain injury (TBI)–induced coagulopathy is a common and well-recognized risk for poor clinical outcomes, but its pathogenesis remains poorly understood, and treatment options are limited ...and ineffective. We discuss the recent progress and knowledge gaps in understanding this lethal complication of TBI. We focus on (1) the disruption of the brain-blood barrier to disseminate brain injury systemically by releasing brain-derived molecules into the circulation and (2) TBI-induced hypercoagulable and hyperfibrinolytic states that result in persistent and delayed intracranial hemorrhage and systemic bleeding.
Summary
Cutaneous wounds are among the most common soft tissue injuries and are particularly hard to heal in aging. Caloric restriction (CR) is well documented to extend longevity; pharmacologically, ...profound rejuvenative effects of CR mimetics have been uncovered, especially metformin (MET), resveratrol (RSV), and rapamycin (RAPA). However, locally applied impacts and functional differences of these agents on wound healing remain to be established. Here, we discovered that chronic topical administration of MET and RSV, but not RAPA, accelerated wound healing with improved epidermis, hair follicles, and collagen deposition in young rodents, and MET exerted more profound effects. Furthermore, locally applied MET and RSV improved vascularization of the wound beds, which were attributed to stimulation of adenosine monophosphate‐activated protein kinase (AMPK) pathway, the key mediator of wound healing. Notably, in aged skin, AMPK pathway was inhibited, correlated with impaired vasculature and reduced healing ability. As therapeutic approaches, local treatments of MET and RSV prevented age‐related AMPK suppression and angiogenic inhibition in wound beds. Moreover, in aged rats, rejuvenative effects of topically applied MET and RSV on cell viability of wound beds were confirmed, of which MET showed more prominent anti‐aging effects. We further verified that only MET promoted wound healing and cutaneous integrity in aged skin. These findings clarified differential effects of CR‐based anti‐aging pharmacology in wound healing, identified critical angiogenic and rejuvenative mechanisms through AMPK pathway in both young and aged skin, and unraveled chronic local application of MET as the optimal and promising regenerative agent in treating cutaneous wound defects.
Amplifying the chemotherapy‐driven immunogenic cell death (ICD) for efficient and safe cancer chemoimmunotherapy remains a challenge. Here, a potential ICD nanoamplifier containing diselenide‐bridged ...mesoporous organosilica nanoparticles (MONs) and chemotherapeutic ruthenium compound (KP1339) to achieve cancer chemoimmunotherapy is tailored. KP1339‐loaded MONs show controlled drug release profiles via glutathione (GSH)‐responsive competitive coordination and matrix degradation. High concentration of MONs selectively evoked reactive oxygen species production, GSH depletion, and endoplasmic reticulum stress in cancer cells, thus amplifying the ICD of KP1339 and boosting robust antitumor immunological responses. After the combination of PD‐L1 checkpoint blockade, cancer cell membrane‐cloaked KP1339‐loaded MONs not only regress primary tumor growth with low systemic toxicity, but also inhibit distant tumor growth and pulmonary metastasis of breast cancer. The results have shown the potential of coordination and redox dual‐responsive MONs boosting amplified ICD for cancer chemoimmunotherapy.
Diselenide‐bridged mesoporous organosilica nanoparticles are selected for coordination and redox dual‐responsive delivery of the chemotherapeutic ruthenium compound KP1339. The cancer cell membrane‐cloaked immunogenic cell death nano‐amplifier performs robust suppression on primary and distant tumor growth, as well as pulmonary metastasis of breast cancer with low systematic toxicity when combined with anti‐PD‐L1.
A new class of large‐but‐flexible Pd‐BIAN‐NHC catalysts (BIAN=acenaphthoimidazolylidene, NHC=N‐heterocyclic carbene) has been rationally designed to enable the challenging Buchwald‐Hartwig amination ...of coordinating heterocycles. This robust class of BIAN‐NHC catalysts permits cross‐coupling under practical aerobic conditions of a variety of heterocycles with aryl, alkyl, and heteroarylamines, including historically challenging oxazoles and thiazoles as well as electron‐deficient heterocycles containing multiple heteroatoms with BIAN‐INon (N,N′‐bis(2,6‐di(4‐heptyl)phenyl)‐7H‐acenaphtho1,2‐dimidazol‐8‐ylidene) as the most effective ligand. Studies on the ligand structure and electronic properties of the carbene center are reported. The study should facilitate the discovery of even more active catalyst systems based on the unique BIAN‐NHC scaffold.
Large‐but‐flexible palladium precatalysts have been rationally designed to enable the challenging Buchwald‐Hartwig amination of coordinating heterocycles. This robust new class of precatalysts permits cross‐coupling of a variety of heterocycles with aryl, alkyl and heteroarylamines, including historically challenging oxazoles and thiazoles as well as electron‐deficient heterocycles containing multiple heteroatoms, under practical aerobic conditions. Studies on the ligand structure and electronic properties of the carbene center are also reported.
A series of Pd–PEPPSI complexes were designed and synthesized. The relationship between catalyst structure and properties was systematically investigated. It was revealed that “bulky‐yet‐flexible” C3 ...bearing ancenaphthyl backbone was a highly efficient precatalyst and could be successfully employed in Suzuki–Miyaura reactions of (hetero)aryl chlorides with (hetero)arylboronic acids at a low palladium loading in the presence of a weak inorganic base in air.
Bulking up: “Bulky‐yet‐flexible” Pd–PEPPSI complexes are developed and found to exhibit high reactivity for Suzuki–Miyaura cross‐coupling reactions. A wide range of biologically relevant bi(hetero)aryls and poly(hetero)aryls are smoothly installed by using a low loading of the palladium catalyst, a weak base, and aerobic conditions. NHC=N‐heterocyclic carbene.
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