Gan Jiang

Central nervous system (CNS) injury is a leading cause of death and long-term disability worldwide. Neurological deficits reflect disruption of central neural circuits. A major barrier to circuit repair is the intrinsically low regenerative potential of adult CNS neurons—linked in part to failure of injury-induced nuclear export of class IIa histone deacetylases (notably HDAC5)—together with a hostile post-injury microenvironment. Here we present a multifunctional nanosystem, encapsulating the class IIa HDAC4/5-selective inhibitor LMK-235 and featuring an electroactive polyaniline coating with asymmetrically distributed 5-hydroxytryptamine moieties. Upon reaching the lesion, our nanosystem assembles into large-pore scaffolds that (i) inhibit the activity of nuclear-retained class IIa HDACs in neurons and thereby reactivate intrinsic regenerative programs, (ii) regulate microglial activation to mitigate neuroinflammation, and (iii) provide an electroactive interface promoting activity-dependent synaptic reconnection. This multi-pronged approach illustrates an integrated platform with translational potential for CNS disorders in which circuit disconnection constrains recovery.

Drug‐induced liver injury (DILI), predominantly caused by acetaminophen (APAP) overdose, is characterized by excessive reactive oxygen species (ROS) production and subsequent hepatocyte necrosis. Although N‐acetylcysteine (NAC) remains the only approved treatment, its effectiveness is limited by a narrow therapeutic time window and reduced efficacy in advanced cases. To address these limitations, an innovative therapeutic approach is developed utilizing ceria's antioxidant properties. In this study, a reconstituted high‐density lipoprotein‐encapsulated ceria nanocatalyst (CeO₂‐rHDL) is engineered to overcome the aggregation tendency and targeting limitation of naked ceria nanoparticles. These findings revealed that CeO₂‐rHDL enters hepatocytes through macropinocytosis, a process synergistically enhanced by both APAP and NAC, facilitating efficient liver targeting. The nanocatalyst demonstrated remarkable therapeutic efficacy by restoring mitochondrial function through ROS reduction. When combined with NAC, CeO₂‐rHDL significantly improved survival outcomes in DILI mice. This lipoprotein‐based nanocatalyst system represents a promising therapeutic strategy for DILI treatment, offering enhanced targeting capabilities and improved therapeutic efficacy.

In the ever-evolving biomedical field, the nano-based drug delivery system has emerged as a revolutionary and transformative force. It has shattered the traditional boundaries of drug delivery, thereby unfurling novel and exciting vistas for the development of highly innovative drug delivery modalities. In recent years, brain-targeting nano drug delivery systems have garnered increasing attention from researchers, clinicians, and the scientific community at large. This newfound focus is primarily attributable to the truly remarkable strides made in both the quantity and quality of related research efforts. Characterized by high brain penetration efficiency, elevated bioavailability, and controlled release properties, these systems hold significant promise for the treatment of central nervous system (CNS) disorders. Nevertheless, it is an inescapable reality that the vast majority is still in the preclinical research phase. The entry of nanocarriers to the brain is limited to such critical challenges as the restrictive blood-brain barrier (BBB), nonspecific distribution, and potential nanotoxicity. Addressing these challenges—particularly improving the efficacy and safety of BBB penetration, enhancing targeting specificity, and optimizing brain clearance mechanisms—remains essential for the clinical translation of these technologies. This review discusses the methods for brain-targeted nano drug delivery systems to overcome BBB, including using brain-targeted ligands to modify nanoparticles to interact with BBB for crossing or repairing BBB, using external physical stimuli to open BBB, and avoiding BBB by entering the brain through peripheral pathways. To further enhance the precision and efficacy of treatment, continuous exploration and breakthroughs are being made in research targeting specific lesions and particular cell subpopulations within the brain. By delving into the distribution, differential characteristics of different brain cell types and their roles in promoting specific brain functions and neuropathological processes, nano-based drug delivery systems can be meticulously designed to achieve precise targeted delivery, thus driving the development of multimodal therapy and personalized medicine. The biocompatibility and safety of nano drug delivery systems are crucial criteria for clinical translation. Therefore, this review also explores the intracerebral fate and clearance mechanisms of nano-based drug delivery systems, aiming to optimize future nano-based drug delivery systems in terms of entering into the brain safely and efficiently, with controllable and precise targeting, and can be metabolized and cleared. Ultimately, we perform a systematic analysis of the research status of these representative nano-based drug delivery systems, especially those that have entered the clinical trial stage or are expected to enter clinical applications. We highly value the mechanisms of entering the brain, therapeutic effects and safety of these systems, aiming to provide a framework for designing more efficient, selective, and biocompatible brain-targeting drug delivery systems to advance the treatment of brain diseases. By doing so, it is hoped that this review will contribute significantly to propelling the development of clinical treatments for brain diseases, bringing new hope and improved outcomes for patients suffering from these debilitating conditions.

Problem-based learning (PBL) in medical education has encountered challenges affecting both teachers and students. The integration of artificial intelligence (AI) into PBL may provide potential solutions to these challenges. This paper aims to discuss the potential advantages of AI, where we found these merits of AI have the potential to improve the quality of PBL lessons. It is also important to pay attention to ethical guidelines and other limitations of AI in PBL lessons as well. Examples of interactions with AI chatbots are provided to demonstrate its application possibility. It is recommended to try using AI in PBL lessons, making it more adaptable for the PBL classroom. Future research should further explore the capabilities of AI, with the goal of developing a more personalized and adaptive learning experience within PBL.

The dismal prognosis for glioblastoma multiform (GBM) patients is primarily attributed to the highly invasive tumor residual that remained after surgical intervention. The development of precise intraoperative imaging and postoperative residual removal techniques will facilitate the gross total elimination of GBM. Here, a self‐disassembling porphyrin lipoprotein‐coated calcium peroxide nanoparticles (PLCNP) is developed to target GBM via macropinocytosis, allowing for fluorescence‐guided surgery of GBM and improving photodynamic treatment (PDT) of GBM residual by alleviating hypoxia. By reducing self‐quenching and enhancing lysosome escape efficiency, the incorporation of calcium peroxide (CaO₂) cores in PLCNP amplifies the fluorescence intensity of porphyrin‐lipid. Furthermore, the CaO₂ core has diminished tumor hypoxia and improves the PDT efficacy of PLCNP, enabling low‐dose PDT and reversing tumor progression induced by hypoxia aggravation following PDT. Taken together, this self‐disassembling and oxygen‐generating porphyrin‐lipoprotein nanoparticle may serve as a promising all‐in‐one nanotheranostic platform for guiding precise GBM excision and empowering post‐operative PDT, providing a clinically applicable strategy to combat GBM in a safe and effective manner.

Nanoparticles (NPs) represent an important advance for delivering diagnostic and therapeutic agents across the blood–brain barrier. However, NP clearance is critical for safety and therapeutic applicability. Here we report on a study of the clearance of model organic and inorganic NPs from the brain. We find that microglial extracellular vesicles (EVs) play a crucial role in the clearance of inorganic and organic NPs from the brain. Inorganic NPs, unlike organic NPs, perturb the biogenesis of microglial EVs through the inhibition of ERK1/2 signalling. This increases the accumulation of inorganic NPs in microglia, hindering their elimination via the paravascular route. We also demonstrate that stimulating the release of microglial EVs by an ERK1/2 activator increased the paravascular glymphatic pathway-mediated brain clearance of inorganic NPs. These findings highlight the modulatory role of microglial EVs on the distinct patterns of the clearance of organic and inorganic NPs from the brain and provide a strategy for modulating the intracerebral fate of NPs.

Matrix metalloproteinases (MMPs) are a class of endopeptidases that are dependent on zinc and facilitate the degradation of extracellular matrix (ECM) proteins, thereby playing pivotal parts in human physiology and pathology. MMPs regulate normal tissue and cellular functions, including tissue development, remodeling, angiogenesis, bone formation, and wound healing. Several diseases, including cancer, inflammation, cardiovascular diseases, and nervous system disorders, have been linked to dysregulated expression of specific MMP subtypes, which can promote tumor progression, metastasis, and inflammation. Various MMP-responsive drug delivery and release systems have been developed by harnessing cleavage activities and overexpression of MMPs in affected regions. Herein, we review the structure, substrates, and physiological and pathological functions of various MMPs and highlight the strategies for designing MMP-responsive nanoparticles to improve the targeting efficiency, penetration, and protection of therapeutic payloads.

Metabolic therapy targeting the metabolic addictions driven by gain-of-function mutations in KRAS is promising in fighting cancer through selective killing of malignant cells without hurting healthy cells. However, metabolic compensation and heterogeneity make current metabolic therapies ineffective. Here, we proposed a biomimetic "Nutri-hijacker" with "Trojan horse" design to induce synthetic lethality in KRAS-mutated (mtKRAS) malignant cells by hitchhiking and reprogramming the metabolic addictions. Nutri-hijacker consisted of the biguanide-modified nanoparticulate albumin that impaired glycolysis and a flavonoid that restrained glutaminolysis after the macropinocytosis of Nutri-hijacker by mtKRAS malignant cells. Nutri-hijacker suppressed the proliferation and spread of mtKRAS malignant cells while lowering tumor fibrosis and immunosuppression. Nutri-hijacker significantly extended the lifespan of pancreatic ductal adenocarcinoma (PDAC)-bearing mice when combined with the hydroxychloroquine-based therapies that failed in clinical trials. Collectively, our findings demonstrated that Nutri-hijacker is a strong KRAS mutation-customized inhibitor and the synthetic lethality based on mtKRAS-driven metabolic addictions might be a promising strategy against PDAC.