Cancer remains the leading cause of mortality worldwide. Radiotherapy (RT), a cornerstone of oncological treatment for over a century, has achieved great success in various cancers. However, radioresistance remains the primary factor leading to the failure of radiotherapy. Histone modifications in cancer cells are known to play a pivotal role in regulating radiosensitivity by modulating chromatin structure, either by loosening or tightening it. Here, we provide a comprehensive summary of the link between aberrant histone modifications and radiation resistance across various cancer and normal tissue cells. Furthermore, we discuss the regulatory mechanisms of histone modifications and the enzymes on the recruitment of proteins that recognize histone modifications. Consequently, these processes substantially affect the radiosensitivity of tumors. In addition to cancer cells, we highlight the intricate interplay between histone modification and radiosensitivity, both within and beyond the cancer cells. Meanwhile, various drugs targeting histone modifications emerge as a promising therapeutic strategy to overcome radioresistance of tumors as well as radioprotection. The combination of histone modification inhibitors with radiotherapy presents a novel approach to enhance cancer treatment outcomes in clinical practice. Nevertheless, the underlying mechanisms through which histone modifications influence cancer radiosen-sitivity require further elucidation to identify novel targets for radiotherapeutic intervention.

Chronic kidney disease (CKD) has emerged as a formidable global health challenge, with a marked increase in its incidence, prevalence, and mortality rates. Renal fibrosis is a central pathophysiological process that drives the progression of CKD to end-stage renal disease. Despite its crucial role in CKD progression, effective clinical interventions to delay or mitigate renal fibrosis remain limited. A deeper understanding of the molecular mechanisms underlying renal fibrosis, along with the identification of potential drug targets and the development of novel therapeutics, holds immense research significance and clinical value for the prevention and treatment of CKD. In recent years, epigenetic research has garnered widespread attention and plays a pivotal role in various disease processes. Against this back-drop, the mechanisms by which epigenetic modifications exert their effects on renal fibrosis are gradually being elucidated, offering novel insights into the understanding of CKD. In this review, we summarize and analyze the intricate regulatory network of epigenetic modifications in renal fibrosis. We explore the promising antifibrotic effects demonstrated by various epigenetically modified drugs in fibrotic kidney models and discuss the challenges and opportunities in current research. These findings provide crucial insights for a deeper understanding of the molecular mechanisms underlying renal fibrosis and the development of novel therapeutic approaches.

Graph neural networks (GNNs) are revolutionizing drug design processes. Over the past five years, GNNs have emerged as transformative tools by accurately modeling molecular structures and interactions with binding targets. Breakthroughs in predicting molecular properties, drug repurposing, toxicity assessment, and interaction analysis, along with generative GNNs enhancing virtual screening and novel molecule design, have significantly sped up drug discovery. These GNN-driven innovations improve predictive accuracy, cut development costs, and reduce late-stage failures. This review focuses on the interdisciplinary integration of GNNs throughout the discovery process, including lead discovery and optimization, synthetic route design, drug–target interaction prediction, and molecular property profiling, while critically evaluating the challenges in translational medicine.

N⁶-methyladenosine (m⁶A) represents the most abundant and functionally significant RNA modification implicated in epigenetic regulation, significantly impacting gene expression through the selective recognition by m⁶A reader proteins. Aberrant expression of m⁶A readers has been associated with cancer progression, contributing to tumor growth, metastasis, drug resistance, and immune evasion. With the increasing research on m⁶A readers, the discovery of small-molecule inhibitors targeting these proteins has emerged as a promising avenue for cancer therapy. This review delineates the classification and functional roles of m⁶A readers across various cancers. Furthermore, we summarize and discuss the recent progress in the development of small-molecule inhibitors, with a focus on the medicinal chemistry perspectives. We hope to provide valuable insights to guide future efforts in drug discovery and rational design targeting m⁶A readers for innovative cancer therapeutics.

Artificial intelligence (AI)-driven data-centric paradigms are catalyzing a paradigm shift in radiopharmaceutical development and molecular imaging, two pivotal technologies that underpin precision nuclear medicine. This review focuses on the cutting-edge applications of AI in radiopharmaceutical discovery and molecular image analytics, and systematically investigates the technical principles and typical cases of Deep Learning algorithms (e.g., Graph Neural Networks (GNNs), Generative Adversarial Networks (GANs), and Transformer Models) in target identification, ligand design, pharmacokinetic optimization, and image reconstruction and enhancement. By integrating multi-omics data and 3D structural information, AI can significantly improve the accuracy of target affinity prediction for radiopharmaceuticals and accelerate the design of novel ligands. In the field of molecular imaging, AI-driven low-dose single-photon emission computed tomography (SPECT) and positron emission tomography (PET) image reconstruction, tumor segmentation, and quantitative analysis techniques have significantly improved the diagnostic efficiency and accuracy, providing a reliable basis for individualized treatment. In addition, the paper discusses data privacy, model generalization, and ethical challenges faced by AI in clinical translation, and looks forward to the future direction of multidisciplinary integration (e.g., combining AI with radiochemistry and nuclear medicine) and technological innovations, which will help precision medicine leap from theory to practice.

Until now, although nanomedicines have gained much success in tumor treatment by reducing severe toxic side effects of drugs and improving the therapeutic efficiency of drugs, they are still faced with thorny challenges in targeted drug delivery including insufficient targeting accuracy, poor penetration into tumor core, and systemic toxicity issues. Recently, engineering nano/microrobots with multiple remarkable properties such as real-time sensing, interacting and manipulating capabilities, and programmability, have received increasing attention in biomedical applications ranging from disease diagnosis, targeted drug delivery, medical imaging, and surgery. More importantly, in different driven modes, nano/microrobots are capable of performing a wide variety of powerful functions, such as enhancing tissue penetration and payload retention in deep-seated tumors with active navigation, being programmable to release drugs or performing specific tasks directly at the tumor site with high precision and accuracy, automating repeated tumor treatment without the need for frequent interventions, and minimizing out-of-target tissue damage, leading to a huge exploration potential in tumor treatment. In this review, we delve into the recent progress and the development direction of nano/microrobots for tumor treatment and emphasize the working mechanisms and the unique functionalities of different driven modes in detail. Meanwhile, we elaborate on the application of nano/microrobots fabricated from various types of materials in tumor therapy. Finally, the key factors to be considered in the clinical translation of the above nano/microrobots are proposed.

Polyethylene glycol (PEG) is a polymer with different molecular weights formed by the polymerization of ethylene oxide monomers. Due to its ability to significantly reduce the immunogenicity of protein drugs and extend their half-life, as well as its high safety profile, it has been approved by the U.S. Food and Drug Administration (FDA) as the gold standard for delivering protein drugs. Although numerous PEGylated protein drugs have been marketed, the focus of research on PEGylated protein drugs has primarily been on reducing immunogenicity and extending in vivo circulation half-life. However, the understanding of how PEG modification affects the structure and function of proteins is still limited, with “activity” often being the sole criterion for evaluating changes in protein structure and function. A deeper exploration of the existence and interaction between PEG chains and proteins is of great significance for understanding the properties exhibited by PEGylated proteins. This review summarizes strategies for PEG site-specific modification of proteins, the interaction states between PEG and proteins, and the effects of PEG chains on protein spatial structure, solubility, activity, and thermal stability. It also summarizes the characterization techniques for PEG–protein interactions, aiming to predict or explain the functions of PEGylated protein drugs through the analysis of PEG–protein interactions.

Bone defects, characterized by a loss of skeletal structure integrity, represent a prevalent clinical challenge affecting millions of patients. While bone autografts and allografts offer potential solutions, limitations, including donor scarcity, immune rejection, anatomical constraints, and complications arising from host comorbidities such as diabetes, often lead to unsatisfactory outcomes. This necessitates the need for alternative treatments. Researchers have identified that reactive oxygen species (ROS) play a crucial role in bone regeneration. Although physiological ROS levels are essential for normal healing, excessive ROS accumulation disrupts the balance between bone formation and resorption, hindering regeneration. Antioxidants can mitigate oxidative stress by scavenging ROS or inhibiting their formation, thereby restoring the equilibrium between bone formation and resorption. Advances in nanotechnology have enabled the development of various ROS-scavenging nanomaterials with enhanced therapeutic efficacy. These nanomaterials either function as delivery platforms for conventional antioxidants or as direct ROS-neutralizing agents through intrinsic redox or enzyme-mimicking properties. This review comprehensively summarizes ROS-scavenging nanomaterials for bone tissue regeneration, focusing on their design strategies, underlying mechanisms, applications, and potential for clinical translation.

The integration of ferroptosis induction with cancer immunotherapy has emerged as a promising approach in oncology, offering dual mechanisms to overcome therapeutic resistance and tumor heterogeneity. Nevertheless, the dynamic and complicated crosstalk between ferroptosis processes and immune regulation in tumor microenvironments presents both opportunities and challenges. By inducing lipid peroxidation in tumor tissues, ferroptotic tumor cell death can stimulate immunogenicity. Nevertheless, excessive lipid peroxidation may paradoxically impair the functionality of multiple immune cells, thereby presenting crosstalk challenges in therapeutic strategies. To address these crosstalk challenges, several advanced drug delivery strategies have been proposed, such as immunostimulatory active pharmaceutical ingredients co-delivery, tumor-targeted delivery, and stimuli-responsive delivery. These drug delivery strategies demonstrate dual therapeutic efficacy by synergistically potentiating ferroptosis induction in malignant cells while concurrently mitigating immunotoxicity and even augmenting antitumor immunity. This review offers detailed insights into the crosstalk between ferroptosis and tumor immunity, along with a guiding overview of the three delivery strategies. The current obstacles and translational potential were thoroughly analyzed, providing valuable perspectives for future research.

Peptide- and protein-based therapeutics offer realized and potential benefits to health, due to their potent bioactivity, high specificity, and favorable safety characteristics. However, their widespread clinical application is constrained by inherent limitations, including rapid enzymatic degradation, poor membrane permeability, and a reliance on parenteral administration, which reduces patient adherence. To overcome these challenges, extensive research has explored non-invasive delivery strategies, including topical, transdermal, and oral formulations. Despite promising advances in these delivery strategies, they are yet to overcome substantial biological and physicochemical barriers in peptide and protein therapeutics, such as enzymatic degradation in the gastrointestinal tract, limited epithelial transport, and inherently low systemic bioavailability. This review provides a comprehensive and up-to-date analysis of the structural and physiological barriers influencing peptide and protein bioavailability and therapeutic efficacy. It critically examines key challenges associated with various administration routes, including topical, transdermal, oral (including delivery targeting the brain), and others. Furthermore, it explores innovative strategies to enhance peptide and protein stability and bioavailability, including chemical modifications, enzyme inhibitors, penetration enhancers, physical delivery technologies, and advanced nanoparticulate formulations. Additionally, emerging trends in formulation optimization, regulatory considerations, and translational pathways for clinical implementation are discussed. By addressing these critical challenges and highlighting recent advances, this review serves as a roadmap for the development of next-generation peptide and protein therapeutics with improved stability and efficacy, and enhanced patient adherence, which is needed to fully realize the true potential of this class of therapeutics.

Glutamine synthetase (GS) in astrocytes regulates glutamatergic neurotransmission by maintaining glutamate clearance in the brain. This study determined that GS in astrocytes of the caudate and putamen (CPu) regulates locomotor sensitization after repeated nicotine exposure. Nicotine increased phosphorylated c-Jun N-terminal kinase (pJNK) by stimulating α7 nicotinic acetylcholine receptors in cultured glioma C6 cells and primary astrocytes in a Ca²⁺-dependent manner. Active JNK phosphorylated metabotropic glutamate receptor 1a (mGluR1a) at the carboxyl terminus of glutathione S-transferase-tagged mGluR1a in vitro. Interference with the pJNK–mGluR1a interaction using the inhibitory peptide, Tat-mGluR1a-i (10 μmol/L), decreased the nicotine-induced increase in GS activity in glioma C6 cells and primary astrocytes. Similar results were obtained by bilateral intra-CPu infusion of the inhibitory peptide (2 nmol/side). Inhibition of GS activity by bilateral intra-CPu infusion of methionine sulfoximine (50 nmol/side) decreased the repeated nicotine-induced increase in locomotor activity. These findings suggest that astrocytes in the CPu upregulate locomotor sensitization by activating GS via the pJNK–mGluR1a interaction, which is linked to α7 nicotinic acetylcholine receptors in response to nicotine.

Metabolic dysfunction-associated steatohepatitis (MASH) is the main cause of end-stage liver disease. We analyzed cell communication via ligand–receptor signaling at the single-cell level to elucidate cell-specific responses and spatial zonation in MASH. We screened and validated Myd88 hyperexpression in liver sinusoidal endothelial cells and liver capsular macrophages (LCM). We showed that Myd88 levels in the periportal endothelial cells of mice with MASH were higher than those in healthy controls, correlating significantly with dysregulation of capillarization markers in vivo. Moreover, Myd88⁺ LCM is a primary source of diverse signaling ligands involved in inflammatory cell recruitment during diet-induced MASH. CD24-Fc bound to the inhibitory receptor SIGLECG to significantly enhance SHP1 binding to MYD88, thereby inhibiting its activation and contributing to the restoration of immune-inflammatory homeostasis in the livers of diet-induced MASH mice. CD24-Fc improved amylin liver nonalcoholic steatohepatitis-induced MASH, which was partly abolished by AAV6-mediated Myd88 knockout in vivo. These findings underscore the central role of MYD88 in MASH etiology, and the specific targeting of MYD88 in liver sinusoidal endothelial cells and LCM may be a potential therapeutic approach to slow the progression of MASH.

Psoriasis is a common inflammatory skin disease with characterization of epidermal hyperplasia and sustained skin inflammation. Long noncoding RNAs (lncRNAs), which contain more than 200 nucleotide-long transcripts, are emerging as the crux of epigenetic regulators in multiple biological processes and diseases. However, how lncRNAs contribute to the etiology of psoriasis remains to be elucidated. For the first time, this study revealed that SNHG15, which was elevated in cytokines-stimulated keratinocytes and psoriasis lesions, promoted keratinocytes hyperproliferation. Mechanistically, SNHG15 fueled epithelial pathology through activation of STAT3/Cyclin D1 axis. Intriguingly, activation of STAT3 enhanced SNHG15 transcription to form a positive feed-back modulatory loop and consequently augmented the skin lesions in psoriasis. Furthermore, knock down the expression of SNHG15 can counteract the IMQ-induced keratinocytes hyperproliferation in vivo. Taken together, our findings uncover that SNHG15 facilitates epidermal hyperplasia via STAT3/Cyclin D1 axis, which might provide a novel therapeutic avenue for psoriasis treatment.

Dysregulation of cytoskeletal proteins has been found in response to DNA damage stress, yet the functional role of cytoskeletal proteins in DNA repair remained unexplored. Here, we found that DNA-damaging agents induced substantial upregulation of smooth muscle-specific cytoskeletal protein smoothelin (SMTN) in colorectal cancer (CRC) cells. Silencing SMTN abrogated G2/M arrest, exacerbated DNA damage, and markedly enhanced the chemosensitivity of CRC cells to various DNA-damaging agents. Notably, SMTN could rapidly accumulate at DNA damage sites within 1 min after laser irradiation, which was indispensable for the initiation of homologous recombination (HR) repair. Mechanistically, SMTN stabilized RAD51 by disrupting its interaction with its E3 ubiquitin ligase HUWE1, thereby maintaining the process of HR repair. To explore the therapeutic role of SMTN, customized cell membrane infused biomimetic liposomes were constructed to ensure rapid delivery of SMTN siRNA specifically into HCT-116 cells, yielding significantly enhanced anti-cancer effects of irinotecan and fuzuloparib both in vitro and in vivo. To summarize, our findings revealed a novel function of SMTN in DNA damage repair and provided a therapeutic strategy of targeting SMTN to enhance the efficacy of DNA damage agents.

Atherosclerosis is a chronic vascular disease closely associated with endothelial dysfunction. Ferroptosis, a major factor in endothelial dysfunction, plays a pivotal role in the progression of atherosclerosis. The development of drugs targeting endothelial ferroptosis offers a potential therapeutic approach for atherosclerosis. This study aimed to assess the potential impact of tetrahydroberberrubine (THBru) on atherosclerosis and unravel its molecular mechanism underlying endothelial protection. Our results demonstrated that THBru significantly reduced plaque formation in the aortas of atherosclerotic mice. Through transcriptome sequencing and further verification, we observed that THBru mitigated endothelial ferroptosis in atherosclerosis by enhancing glutathione homeostasis and decreasing reactive oxygen species (ROS) accumulation. Mechanistically, bioinformatic analysis demonstrated that THBru reduced the expression of the super-enhancer (SE) regulatory gene ATP-binding cassette subfamily C member 1 (ABCC1). The transcription factor BTB and CNC homology 1 (BACH1) was responsible for ABCC1 transcription by binding to its SE (ABCC1-SE), whereas THBru effectively inhibited the activity of ABCC1-SE. Furthermore, THBru promoted adenosine monophosphate-activated protein kinase (AMPK) activation, thereby negatively regulating BACH1 and the downstream ABCC1/ferroptosis signaling pathway. Collectively, these findings highlight THBru as a promising candidate for treating atherosclerosis, featuring a novel mechanism that inhibits endothelial ferroptosis through the AMPK/BACH1 axis to regulate ABCC1-SE.

The ischemic penumbra is critical in acute ischemic stroke (AIS) treatment, yet the regulation of precise RNA modification pathways remains unclear. Using a mouse model of ischemic stroke and human postmortem brain samples, we demonstrate that N⁶-methyladenosine (m⁶A) levels are elevated in neurons within the ischemic penumbra. Notably, m⁶A modifications by m⁶A reader protein IGF2BP1 were enriched on penumbra related circular RNA derived from oxoglutarate dehydrogenase (CircOGDH). IGF2BP1 stabilizes CircOGDH by recruiting it to stress granules, maintaining high expression in the ischemic penumbra. Knockdown of IGF2BP1 reduced CircOGDH stability and decreased neuronal apoptosis under hypoxic conditions, suggesting a protective role. Igf2bp1 knockdown also preserved synaptic integrity in MCAO mice, with increased expression of synaptic markers and improved synaptic morphology. Importantly, Igf2bp1 knockdown significantly reduced penumbra volume compared to CircOGDH inhibition alone. These findings highlight IGF2BP1 as a promising therapeutic target for modulating penumbra-related RNA expression and promoting recovery in AIS.

Psoriasis is a common immune-mediated skin disorder manifesting in abnormal skin plaques, and remains a challenge in its management. Blocking the release or inflammatory effects of two proinflammatory molecules of the S100-alarmin family, S100A8 and S100A9, in keratinocytes is a promising strategy for future therapeutic approaches. Undulanoids A-D (1-4), four novel sesterterpenoids possessing a highly congested pentacyclic 6/5/5/6/5 ring system with eight stereogenic centers, including three all-carbon quaternary centers, two quaternary carbon centers at the bridgehead, and a 1,4,11-trimethyltricyclo[5.3.1.0^4,11]undecane fragment, were isolated from Aspergillus undulatus. Their structures were elucidated by spectroscopic data and single-crystal X-ray diffraction. Strikingly, undulanoid B (2), the most promising lead compound, inhibits the expression of genes related to tumor necrosis factor and interleukin-17 signaling pathways. Furthermore, reverse target prediction, cellular thermal shift assay, and dynamic simulation indicated that compound 2 could target with the expression of S100A9 and keratinocyte proliferation. As the pioneering S100A8/A9 complex and inhibit its secretion. Moreover, compound 2 showed a potent therapeutic effect on the psoriasiform skin lesions induced by imiquimod in mice by inhibiting the expression of S100A9 and keratinocyte proliferation. As the pioneering examples of natural products demonstrate inhibitory action against S100A8/A9 complex, this discovery provides a series of compelling lead compounds with novel molecular scaffold for treating psoriasis.

Degrader–antibody conjugates (DACs) represent a promising drug modality for targeting hematological malignancy, but still lack rational design frameworks. Here, we show the strategies of reasonable antibody-degrader compatibility and degradation tail-derived conjugatability through a systematic exploration. Inspired by the success of IKZF1/3 degraders, we sought to explore the potential of cereblon E3 ligase modulators (CELMoDs) in constructing novel conjugates. By combining a modular library with neo-substrate screening and further conjugatable derivation, I034 was identified, a potent CELMoD payload with picomolar degradation activity and antiproliferative effects. Through linker chemistry, I034-based DACs were constructed and demonstrated superior efficacy and safety compared to auristatin-based conjugates both in vitro and in vivo, with the CD38-targeting Dara-VA-I034 achieving complete tumor eradication at low doses. Mechanistic insights revealed distinct positive feedback regulation of CD38 conjugates, highlighting the need for compatibility between payloads and antigens. These results demonstrate that the approach could provide a framework for discovering CELMoD payloads and advancing DACs for treating multiple myeloma and other malignancies.

Cyclic AMP-response element binding protein (CREB), a downstream transcription factor of multiple signaling pathways, is overexpressed in many different types of cancers. Thus, targeting CREB has great potential for the development of antitumor agents. Peptidic foldamers have emerged as a powerful tool to disrupt disease-related protein–protein interactions (PPIs) with chemodiversity and high stability towards enzymatic degradation. Herein, we harnessed several hydrophobic groups of helical sulfonyl-γ-AApeptide foldamer targeting the hydrophobic grooves on the surface of the KIX domain of CREB binding protein (CBP), to disrupt CREB/CBP PPI. We showed that several stapled sulfonyl-γ-AApeptides could suppress CREB-mediated gene transcription and exhibit effective antiproliferative activity in cell-based assays and demonstrate its potency in inhibiting tumor growth in vivo. Our studies suggest that sulfonyl-γ-AApeptides as a class of helical foldamer could mimic the helical kinase-inducible activation domain of CREB (KID) to target the hydrophobic grooves on the surface of CBP KIX domain, and thereby inhibiting KIX–KID interaction, which provides a new strategy for the development of antitumor agent by targeting PPIs involving intrinsically disordered proteins (IDPs).

The bromodomain-containing protein 9 (BRD9) is a core subunit of mammalian SWI/SNF chromatin remodeling complex termed ncBAF. BRD9 has emerged as a potential target for anticancer drugs, particularly in the treatment of acute myeloid leukemia (AML). Herein, we reported 10m (Y22073) and 10t as new BRD9 selective bromodomain inhibitors. Crystallographic studies revealed that the key active imidazolyl group discovered from structure-activity relationship (SAR) can induce Phe163 flipping and significantly enhance the cellular potency of the compounds, making 10m the first BRD9 selective inhibitor with significant cellular activity against AML cells. We also validated the critical role of imidazolyl groups by modifying existing BRD9 inhibitors. The representative compounds 10m and 10t demonstrated potent binding affinity, outstanding selectivity toward BRD9 bromodomain, and significantly inhibited the proliferation of AML cell lines. 10m also showed good metabolic stability, solubility and pharmacokinetic properties. Additionally, oral administration of compounds 10m and 10t exhibited potent anti-tumor efficacy in the MV4-11 xenograft mouse model. The potent, selective, and orally available BRD9 bromodomain inhibitors may address the challenges of weak cellular activity and limited phenotypic efficacy faced by BRD9 inhibitors, and serve as new lead compounds for the development of anticancer agents for the treatment of AML.

Probiotic therapy offers a promising strategy for chronic infected wound management through pathogen suppression and immune modulation. However, its efficacy remains restricted by weak competitiveness in pathogen-rich niches and poor penetration across biofilm barriers. Inspired by bacterial competitive interactions, we developed a multifunctional microneedle (MN) platform to overcome these limitations. Lactobacillus reuteri (Lr) was coated with poly-l-lysine-modified metal–phenolic networks (MPNs) encapsulating doxorubicin (DOX), yielding DOX@MPN–PLL@Lr (DMP@Lr). The engineered probiotics were incorporated into dissolving MNs enriched with nutrient broth to ensure excellent microneedle performance and probiotic function. This design leverages MPN multifunctionality to reduce early-stage pathogenic burden via photothermal-assisted bacterial killing and near-infrared (NIR)-promoted antibiotic release, thereby enhancing probiotic competitiveness. Meanwhile, MNs physically disrupt biofilms for precise delivery into deep infection sites. In vitro, DMP@Lr achieved >99.9% (5.5 log) bactericidal efficiency, and its MNs exhibited a 1.4-fold higher biofilm clearance compared with blank MNs. In vivo, a single DMP@Lr MN patch promoted 93.9% wound closure, demonstrating potent antibacterial activity and accelerated healing. This study presents an innovative, translatable probiotic-based MN therapy for the effective treatment of chronically infected wounds.

Atopic dermatitis (AD) is a prevalent cutaneous condition with chronic inflammation and immune dysregulation, posing a public health concern owing to its long-lasting and recurrent nature. Butyrate, a short-chain fatty acid produced by gut microbiota, exhibits significant anti-inflammatory effects in AD. Yet, its delivery via butyrylated starch for prolonged release in the colon has not been adequately investigated. In this study, butyrylated Smilax glabra starch (BSGS) was synthesized and its therapeutic potential against AD via modulation of the gut–skin axis was examined. BSGS exhibited a C-type crystalline structure and highly resistance to gastrointestinal digestion. In vitro anaerobic fermentation showed that BSGS effectively promoted the generation of short-chain fatty acids, especially butyrate, and positively influenced the gut microbial composition. In AD mice, BSGS administration considerably mitigated cutaneous inflammation, lowered serum proinflammatory cytokines, restored intestinal barrier integrity, and modulated gut microbiota by increasing Bacteroides and norank_f__Prevotellaceae while decreasing Alistipes and norank_o__RF39. This therapeutic effect was associated with butyrate release and NF-κB pathway suppression, as evidenced by the reduced phosphorylation of p65 and IκBα. These findings establish that BSGS, a novel colon-targeted butyrate donor, holds promising potential in AD treatment by modulating the immune system via the gut–skin axis.

The kidneys are susceptible to hypoxia, proteinuria, and toxins, which can trigger acute kidney injury (AKI). Maladaptive repair of AKI results in the development of chronic kidney disease (CKD). Epithelial-mesenchymal transition (EMT) represents a pivotal mechanism underlying renal interstitial fibrosis (RIF). Myofibroblasts represent the primary effector cells of RIF with over 30% derived from renal tubular epithelial cells (RTECs). RTECs play a crucial role in CKD by generating part of EMT, while Snail1 is an effective inducer of EMT. Therefore, silencing Snail1 in RTECs and blocking the EMT process represents an original approach for treating RIF. Here, the positively charged l-arginine (L-Arg) and the hydrophobic fragment stearic acid (SA) were introduced on the chitosan oligosaccharide to afford a dual-targeted COA-SA micelle via size-, charge- and active targeting effects. The micelle overcomes the substantial disparity in physical and chemical properties between hydrophilic nucleic acid macromolecules and the anti-inflammatory small molecule celastrol and successfully establishes a codelivery platform. In vivo, COA-SA micelles can traverse the blood circulation, and glomerular filter, and overcome intracellular barriers to achieve efficient and precise drug delivery to RTECs. This results in the successful reversal of the EMT process in RTECs, thereby achieving a favorable anti-fibrosis effect.

The clinical translation of catalytic therapy has been hindered in recent decades due to immunological risks, delayed degradation, and poorly understood metabolism associated with catalysts, despite promising results in antitumor therapy. Developing catalysts with nonmetallic active centers may provide an alternative to those with metallic active centers. In this study, a natural protein nanocatalyst, Hb@PtPP, is developed through the moderate polymerization of pyrrole and hemoglobin for tumor catalytic therapy. In comparison with BSA@PtPP prepared from bovine serum albumin, Hb@PtPP exhibits distinctive autoxidation activity in tumor cells in response to elevated hydrogen peroxide levels while maintaining relatively low activity in normal cells. This feature enables Hb@PtPP to effectively combat tumors by initiating a cascade of catalytic reactions, including the production of reactive oxygen species, the release of heme and iron ions, and the accumulation of lipid peroxidation, all of which contribute to apoptosis and ferroptosis in tumor cells. RNA-sequencing results further demonstrate that tumor cells undergo ferroptosis. Additionally, these catalytic processes are augmented by the photothermal effect, resulting in efficient tumor killing and growth inhibition both in vitro and in vivo. This study underscores the crucial role of hemoglobin in advancing catalytic therapy for tumors.

Retinoblastoma (RB) is the most common primary ocular malignancy in children, arising from the developing retina. While higher doses of local chemotherapy have improved tumor control, concerns regarding retinal toxicity and the development of chemoresistance remain significant. Oncolytic adenovirus (OA) presents a promising therapeutic approach for RB, but rapid clearance often limits its therapeutic effects. In this study, we engineered a genetically modified OA derived from human adenovirus 5 (Ad5), designed to selectively target and lyse RB cells. The combination of OA with low-dose melphalan demonstrates an enhanced antitumor effect, while minimizing retinal toxicity. In vitro and in vivo experiments demonstrated that melphalan significantly enhanced the antitumor effect of OA and extended ocular survival. More importantly, we developed a biocompatible injectable hydrogel delivery system based on the covalent coupling of collagen and aldehyde-modified cyclodextrin, which effectively enhances the loading efficiency of melphalan and enables sustained co-delivery of OA and melphalan. The mouse RB tumor model confirmed that this hydrogel system (OA-Mel@CCA) achieved localized and sustained delivery of both therapeutics, effectively controlling tumor growth and preventing brain metastasis. Additionally, retinal structure and function were notably preserved in mice treated with OA-Mel@CCA, with no observed retinal toxicity. These findings suggest that the injectable hydrogel-based co-delivery of melphalan and oncolytic adenovirus could represent a promising strategy for RB treatment.

Programmed cell death protein-1/programmed cell death ligand-1 (PD1/PD-L1) blockade has shown promise in cancer therapy but remains limited by low response rates. Recent efforts have explored strategies to enhance immunotherapy efficacy. Histone lysine-specific demethylase 1 (LSD1) inhibition can enhance tumor immune responses by downregulating PD-L1 expression. Furthermore, PD-L1 in tumor cell-derived extracellular vesicles (EVs) contributes to the immunosuppressive tumor microenvironment (TME) and promotes immune evasion. Here, we found that LSD1 inhibition can mediate the rearrangement of PD-L1 on tumor cell surfaces, reduce the secretion of EVs and PD-L1 levels in the TME, and ultimately block the long-range immunosuppression caused by tumor cell-released EVs. Therefore, we developed a TME-targeted synergistic therapy system with a dual mechanism in which anti-PD1 therapy blocks immune checkpoints, and forsythiaside A (FA) acts as an LSD1 inhibitor to regulate EVs secretion. Additionally, CD4⁺ T cells can directly kill tumor cells by inducing G1/S cell cycle arrest. Ultimately, this system activates the tumor immune response within the TME, effectively inhibiting the growth of non-small cell lung cancer tumors. Our work highlights the signaling role of EVs and the capacity of CD4⁺ T cells to arrest the cell cycle, offering a new approach to enhance response to anti-PD1/PD-L1 therapy.

Idiopathic pulmonary fibrosis (IPF) is a complex interstitial lung disease in which myofibroblasts are the primary effector cells. FK506-binding protein (FKBP10), a procollagen chaperone, is upregulated in IPF and primarily localizes to myofibroblasts. Exosomes have garnered significant attention as novel drug delivery vehicles, particularly when engineered. However, myofibroblasts remain underexplored in terms of engineered exosome-based therapies and associated drug targets. In this study, RDYH58, a peptide that targets myofibroblasts, was conjugated to the exosomal membrane protein Lamp2b to produce RDYH58-linked exosomes (RDYH58-exo). In vitro and in vivo experiments demonstrated that compared to unmodified exosomes (unm-exo), RDYH58-exo preferentially localized to myofibroblasts. A small interfering RNA targeting FKBP10 (siFKBP10) was loaded into exosomes using ultrasonic microfluidics method, and the antifibrotic effects of RDYH58-exo carrying siFKBP10 (RDYH58-siFKBP10) were assessed both in vitro and in vivo. The results demonstrated that RDYH58-siFKBP10 effectively silenced FKBP10 gene expression, significantly inhibiting fibroblast activation and extracellular matrix deposition, with superior antifibrotic efficacy compared to unmodified exosome vectors (unm-siFKBP10). RNA-seq analysis confirmed the pivotal regulatory role of FKBP10, providing critical evidence for the development of targeted therapeutic strategies. The RDYH58-siFKBP10 delivery system developed in this study demonstrates remarkable clinical translation potential.

The deposition characteristics of nasal formulations directly determine the efficacy of the drugs, whilst the complexity of human nasal airway structure encumbers quantitative evaluation of nasal spatial deposition. Male and female standard nasal airway structure models were calculated from computed tomography data of 128 Chinese Han nationality using statistical shape model. The deposition evaluation devices were further designed, and an imaging method was then employed to obtain drug deposition information. Furthermore, drug spatial deposition atlases were proposed by UV unwrapping, a mathematical mapping procedure flattening three-dimensional (3D) information to two-dimension bidirectionally, to achieve quantification of drug deposition fractions in the regions of interest. Moreover, the feasibility and universality of this method were verified by correlating it with the chemical quantitative results and computational fluid dynamic simulation of drug deposition of mometasone furoate nasal spray and hydroxypropyl methylcellulose nasal powder, respectively. Finally, the unique drug spatial deposition atlases of these two formulations in the male and female evaluation devices were generated, respectively. In summary, the standard nasal airway structure models of the Chinese Han nationality and the drug spatial deposition atlases provide scientific tools for the formulation optimization and quality control of nasal formulations.

Monoacylglycerol lipase (MAGL) constitutes a crucial serine hydrolase within the endocannabinoid system, which has been suggested as a potential therapeutic target for the treatment of various neurodegenerative disorders. While MAGL inhibitors have entered the clinical arena, a highly selective and MAGL-specific positron emission tomography (PET) ligand holds promise to significantly facilitate clinical drug development by allowing the quantification of MAGL levels and the assessment of target occupancy in patients. Accordingly, this study aimed to develop a new series of reversible MAGL inhibitor candidates, based on a piperazinyl azetidine diamide scaffold. Compound 3 demonstrated the most promising performance characteristics in pharmacological evaluations compared to other MAGL inhibitor candidates. Subsequently, it was labeled with fluorine-18 and further assessed through autoradiography and PET imaging, as well as ex vivo biodistribution and metabolite analysis experiments in rodents. Compound 3 exhibited a heterogeneous radioactivity distribution, favorable brain uptake, and excellent in vivo binding specificity. Target occupancy studies with a therapeutic MAGL inhibitor demonstrated a dose-dependent PET signal reduction of [¹⁸F]3 in rat brains. In conclusion, [¹⁸F]3 ([¹⁸F]MAGL-2011) has the potential to serve as an effective MAGL PET ligand.