Microneedles have demonstrated value in targeted treatment of dermatosis. Current investigation aims to enhance the functions and optimize substance delivery to improve therapeutic effects. Here, we present innovative shell–core microneedles with light-pH dual responsiveness for spatiotemporal sequential release of multiple Chinese herb drugs to treat scleroderma. By using a stepwise template-assisted method, we effectively prepare a hydrogel-based core layer containing polydopamine-MXene (P-MXene) loaded with triptolide (TP), and a shell layer composed of polyvinyl alcohol (PVA) encapsulating paeoniflorin (Pae). P-MXene can adsorb the sparingly soluble TP to ensure its encapsulation efficiency and contribute to the synergistic photothermal effect benefitting from its excellent photothermal conversion ability. Besides, PVA can rapidly dissolve upon microneedle piercing into the skin and quickly release the anti-inflammatory and detoxifying Pae, establishing a favorable low-acid subcutaneous environment. In response to pH changes and near-infrared effects, TP is sustainably released from P-MXene and delivered through the swollen pores of the hydrogel. On the basis of these characteristics, we demonstrate that these microneedles could effectively reduce profibrotic key cytokines interleukin-1β and transforming growth factor-β, thereby reducing collagen deposition and decreasing epidermal thickness, ameliorating skin fibrosis and capillary lesion in scleroderma mouse models. These findings highlight the important clinical potential of these microneedles in the treatment of skin diseases.

Extracellular vesicles (EVs) are lipid bilayer-enclosed vesicles released by cells. EVs encapsulate proteins and nucleic acids of their parental cell and efficiently deliver the cargo to recipient cells. These vesicles act as mediators of intercellular communication and thus play a crucial role in various physiological and pathological processes. Moreover, EVs hold promise for clinical use. They have been explored as drug delivery vehicles, therapeutic agents, and targets for disease diagnosis. In the landscape of cancer research, while strides have been made in EV-focused cancer physiopathology, liquid biopsy, and drug delivery, the exploration of EVs as immunotherapeutic agents may not have seen substantial progress to date. Despite promising findings reported in cell and animal studies, the clinical translation of EV-based cancer immunotherapeutics encounters challenges. Here, we review the existing strategies used in EV-based cancer immunotherapy, aiming to propel the development of this emerging yet crucial field.

Cell culture as the cornerstone of biotechnology remains a labor-intensive process requiring continuous manual oversight and substantial time investment. In this work, we propose an integrated mini-pillar platform for in situ monitoring of multiple cellular metabolism processes, which achieves media anchoring and cell culture through an arrayed mini-pillar chip. The assembly of polyaniline (PANI)/dendritic gold-modified microelectrode biosensors exhibits high sensitivity (63.55 mV/pH) and excellent interference resistance, enabling real-time acquisition of biosensing signals. We successfully employed such integrated devices to real-time measuring pH variations in multiple cells and real-time monitoring of cell metabolism under drug interventions and to facilitate in situ assisted cultivation of 3-dimensional (3D) cell spheroids. This mini-pillar array-based cell culture platform exhibits excellent biosensing sensitivity and real-time monitoring capability, offering considerable potential for the advancement of biotechnology and medical drug development.

Golgi protein 73 (GP73), a resident protein of the Golgi apparatus, is notably elevated in hepatocellular carcinoma (HCC). While its critical role in remodeling the tumor microenvironment (TME) is recognized, the intricate mechanisms are not fully understood. This study reveals that GP73 in HCC cells interacts with prolyl hydroxylase-2 (PHD-2) in a competitive manner, thereby impeding the hydroxylation of hypoxia-induced factor-1α (HIF-1α). The effect above promotes the production and secretion of vascular endothelial growth factor A (VEGFA). Moreover, exosomal GP73 derived from HCC cells can be internalized by human umbilical vein endothelial cells (HUVECs) and competitively interact with HECTD1, an E3 ubiquitin ligase targeting growth factor receptor-bound protein 2 (GRB2). This interaction stabilizes GRB2, thereby activating the Ras–mitogen-activated protein kinase (MAPK) signaling pathway. Consequently, escalated levels of GP73 intensify VEGF production in HCC cells and potentiate mitogenic signaling in vascular endothelial cells, fostering angiogenesis in the TME. Our findings propose that GP73 might serve as a novel target for anti-angiogenic therapy in HCC.

Lung cancer is the second most commonly diagnosed cancer and a leading cause of cancer-related death, with non-small cell lung cancer (NSCLC) being the most prevalent type. Over 70% of lung cancer patients require radiotherapy (RT), which operates through direct and indirect mechanisms to treat cancer. However, RT can damage healthy tissues and encounter radiological resistance, making it crucial to enhance its precision to optimize treatment outcomes, minimize side effects, and overcome radioresistance. Integrating nanotechnology into RT presents a promising method to increase its efficacy. This review explores various nano-assisted RT strategies aimed at achieving precision treatment. These include using nanomaterials as radiosensitizers, applying nanotechnology to modify the tumor microenvironment, and employing nano-based radioprotectors and radiation-treated cell products for indirect cancer RT. We also explore recent advancements in nano-assisted RT for NSCLC, such as biomimetic targeting that alters mesenchymal stromal cells, magnetic targeting strategies, and nanosensitization with high-atomic number nanomaterials. Finally, we address the existing challenges and future directions of precision RT using nanotechnology, highlighting its potential clinical applications.

Rapid diagnosis and real-time monitoring are of great important in the fight against cancer. However, most available diagnostic technologies are time-consuming and labor-intensive and are commonly invasive. Here, we describe CytoExam, an automatic liquid biopsy instrument designed based on inertial microfluidics and impedance cytometry, which uses a deep learning algorithm for the analysis of circulating tumor cells (CTCs). In silico and in vitro experiments demonstrated that CytoExam could achieve label-free detection of CTCs in the peripheral blood of cancer patients within 15 min. The clinical applicability of CytoExam was also verified using peripheral blood samples from 10 healthy donors and >50 patients with breast, colorectal, or lung cancer. Significant differences in the number of collected cells and predicted CTCs were observed between the 2 groups, with variations in the dielectric properties of the collected cells from cancer patients also being observed. The ultra-fast and minimally invasive features of CytoExam may pave the way for new paths for cancer diagnosis and scientific research.

Micro/nanorobots (MNRs) are envisioned to provide revolutionary changes to therapies for infectious diseases as they can deliver various antibacterial agents or energies to many hard-to-reach infection sites. However, existing MNRs face substantial challenges in addressing complex infections that progress from superficial to deep tissues. Here, we develop swarming magnetic Fe₃O₄@polydopamine-tannic acid nanorobots (Fe₃O₄@PDA-TA NRs) capable of performing targeted bacteria elimination in complicated bacterial infections by integrating superficial photothermal and deep chemical strategies. The Fe₃O₄@PDA-TA nanoparticles (NPs), serving as building blocks of the nanorobots, are fabricated by in situ polymerization of dopamine followed by TA adhesion. When driven by alternating magnetic fields, Fe₃O₄@PDA-TA NPs can assemble into large energetic microswarms continuously flowing forward with tunable velocity. Thus, the swarming Fe₃O₄@PDA-TA NRs can be navigated to achieve rapid broad coverage of a targeted superficial area from a distance and rapidly eradicate bacteria residing there upon exposure to near-infrared (NIR) light due to their efficient photothermal conversion. Additionally, they can concentrate at deep infection sites by traversing through confined, narrow, and tortuous passages, exerting sustained antibacterial action through their surface TA-induced easy cell adhesion and subsequent membrane destruction. Therefore, the swarming Fe₃O₄@PDA-TA NRs show great potential for addressing complex superficial-to-deep infections. This study may inspire the development of future therapeutic microsystems for various diseases with multifunction synergies, task flexibility, and high efficiency.

The tricarboxylic acid (TCA) cycle is capable of providing sufficient energy for the physiological activities under aerobic conditions. Although tumor metabolic reprogramming places aerobic glycolysis in a dominant position, the TCA cycle remains indispensable for tumor cells as a hub for the metabolic linkage and interconversion of glucose, lipids, and certain amino acids. TCA intermediates such as citrate, α-ketoglutarate, succinate, and fumarate are altered in tumors, and they regulate the tumor metabolism, signal transduction, and immune environment to affect tumorigenesis and tumor progression. This article provides a comprehensive review of the modifications occurring in tumor cells in relation to the intermediates of the TCA cycle, which affects tumor pathogenesis and current therapeutic strategy for therapy through targeting TCA cycle in cancer cells.

Messenger RNA (mRNA) has emerged as an innovative therapeutic modality, offering promising avenues for the prevention and treatment of a variety of diseases. The tremendous success of mRNA vaccines in effectively combatting coronavirus disease 2019 (COVID-19) evidences the unlimited medical and therapeutic potential of mRNA technology. Overcoming challenges related to mRNA stability, immunogenicity, and precision targeting has been made possible by recent advancements in lipid nanoparticles (LNPs). This review summarizes state-of-the-art LNP-mRNA-based therapeutics, including their structure, material compositions, design guidelines, and screening principles. Additionally, we highlight current preclinical and clinical trends in LNP-mRNA therapeutics in a broad range of treatments in ophthalmological conditions, cancer immunotherapy, gene editing, and rare-disease medicine. Particular attention is given to the translation and evolution of LNP-mRNA vaccines into a broader spectrum of therapeutics. We explore concerns in the aspects of inadequate extrahepatic targeting efficacy, elevated doses, safety concerns, and challenges of large-scale production procedures. This discussion may offer insights and perspectives on near- and long-term clinical development prospects for LNP-mRNA therapeutics.

Platelet activation contributes to sepsis development, leading to microthrombosis and increased inflammation, which results in disseminated intravascular coagulation and multiple organ dysfunction. Although Cathelicidin can alleviate sepsis, its role in sepsis regulation remains largely unexplored. In this study, we identified Cath-HG, a novel Cathelicidin from Hylarana guentheri skin, and analyzed its structure using nuclear magnetic resonance spectroscopy. The modulatory effect of Cath-HG on the symptoms of mice with sepsis induced by cecal ligation and puncture was evaluated in vivo, and the platelet count, degree of organ damage, and microthrombosis were measured. The antiplatelet aggregation activity of Cath-HG was studied in vitro, and its target was verified. Finally, we further investigated whether Cath-HG could regulate thrombosis in vivo in a FeCl₃ injury-induced carotid artery model. The results showed that Cath-HG exhibited an α-helical structure in sodium dodecyl sulfate solution and effectively reduced organ inflammation and damage, improving survival in septic mice. It alleviated sepsis-induced thrombocytopenia and microthrombosis. In vitro, Cath-HG specifically inhibited collagen-induced platelet aggregation and modulated glycoprotein VI (GPVI) signaling pathways. Dot blotting, enzyme-linked immunosorbent assay, and pull-down experiments confirmed GPVI as the target of Cath-HG. Molecular docking and amino acid residue truncations/mutations identified crucial sites of Cath-HG. These findings suggest that GPVI represents a promising therapeutic target for sepsis, and Cath-HG may serve as a potential treatment for sepsis-related thrombocytopenia and thrombotic events. Additionally, identifying Cath-HG as a GPVI inhibitor provides insights for developing novel antithrombotic therapies targeting platelet activation mediated by GPVI.