Abstract Ulcerative colitis (UC) is a chronic recurrent inflammatory bowel disease characterized by abdominal pain, hematochezia, and weight loss. Although remarkable progress has been made toward understanding the pathogenesis of UC, finding more effective treatments for this disease remains a challenge. Interleukin‐10 (IL‐10) possesses potent anti‐inflammatory properties, yet its therapeutic application in UC has failed clinically due to poor targeting and a short half‐life. In this study, we developed IL‐10‐secreting engineered macrophages (IL‐10M) based on RAW264.7 cells and evaluated their therapeutic effects in a dextran sulfate sodium‐induced colitis model. Intraperitoneal administration of IL‐10M alleviated body weight loss, disease activity, colon shortening, and histological injury. IL‐10M also reduced mucosal damage and improved tight junction‐associated epithelial barrier markers. Flow cytometry further detected engineered macrophage‐associated GFP signals in colonic tissues and revealed an early increase in CD206 + endogenous colonic macrophages. Microbiome profiling showed treatment‐associated compositional changes, including alterations in Bacteroides acidifaciens and Mucispirillum schaedleri , indicating microbiota remodeling after engineered macrophage treatment. Short‐term safety assessment did not reveal overt hematological abnormalities or major histological injury in liver and spleen. Overall, these findings suggest that IL‐10‐secreting engineered macrophages may represent a promising macrophage‐based strategy for mitigating intestinal inflammation in experimental colitis.
Abstract Messenger RNA (mRNA) therapeutics formulated in lipid nanoparticles (LNPs) have transformed the field of nucleic acid medicine by enabling transient, programmable protein expression for vaccination, protein replacement, immunotherapy, and genome engineering. Extending their clinical success beyond vaccines requires a mechanistic understanding of where LNP components and mRNA travel, which cells they enter, where cargo is translated, and how each component is cleared. Such biodistribution outcomes are governed by a complex interplay between nanoparticle physicochemical properties, administration route, protein corona formation, host physiology, intracellular trafficking, and degradation. Importantly, the biodistribution of lipid components, intact mRNA, degraded RNA fragments, and translated proteins represents distinct yet interconnected biological processes that should not be interpreted interchangeably. Advances in molecular imaging, quantitative nucleic acid analysis, mass spectrometry, spatial and single‐cell technologies, and pharmacokinetic modeling are improving their resolution across tissues and time. In parallel, rational lipid engineering, selective organ targeting, biodegradable ionizable lipids, ligand‐directed delivery, and artificial intelligence‐assisted design are expanding opportunities for tissue‐specific delivery beyond the liver and lymphoid organs. However, interpretation remains constrained by assay heterogeneity, incomplete understanding of protein corona dynamics and endosomal escape, species‐dependent differences, and the absence of harmonized regulatory standards. This review examines the mechanisms governing mRNA‐LNP disposition, evaluates what current analytical methods detect and miss, synthesizes preclinical and clinical evidence, and considers the strategies needed to achieve predictable, tissue‐selective, and clinically translatable mRNA delivery.
Abstract Osteogenesis is a crucial process in bone injury repair where osteoblasts mineralize collagen to form new bone at the fracture site. For effective bone regeneration in comminuted fractures, it is essential to develop an osteogenic bone adhesive that can be applied at the time of fixation to temporarily immobilize fragmented bone pieces. We present a flowable, injectable adhesive that enables on‐demand bonding of irregular fracture surfaces and, after photocuring, provides enhanced mechanical integrity while supporting osteogenesis. To meet these clinical requirements, we engineered a gelatin methacryloyl–polyethylene glycol diacrylate (GelMA–PEGDA) network bone adhesive that undergoes rapid photocuring to enable on‐demand bonding and immediate mechanical stabilization at the fracture site. By incorporating nanoscale hydroxyapatite (nHA) to confer a bone‐mineral‐mimetic composition and biomineralization capacity, the photocured adhesive promotes bone marrow‐derived mesenchymal stem cell recruitment and supports skeletal regeneration. During degradation, the organic–inorganic phase of the adhesive can guide osteogenesis, leading to satisfactory healing outcomes in fractures. Overall, the compositional and mechanical biomimicry, photosensitivity and osteogenic potential of GelMA–nHA–PEGDA render it a potential all‐in‐one solution for minimally invasive treatment of multiple skeletal diseases.
Abstract Intra‐arterial chemotherapy (IAC) for hepatocellular carcinoma (HCC) is limited by the escape of chemotherapeutic agents into systemic circulation, causing severe side effects such as heart failure. This study aims to develop and optimize endovascular magnetic filtration devices to enhance IAC efficacy, by targeted removal of excess drug‐coated ultrasmall superparamagnetic iron oxide (USPIO) particles from circulation. Device performance was evaluated through multi‐physics simulations that coupled the transport of drug‐coated magnetic particles in blood flow with magnetic interactions and magnetophoretic forces. A dimensional analysis framework was applied to characterize particle capture efficiency () across alternative device designs, and numerical predictions were compared with published benchtop experiments. Optimized multi‐stage filters achieved up to ~80% predicted capture efficiency, while reducing the risk of intravascular device collapse. These results demonstrate a novel strategy for reducing systemic toxicity in IAC through endovascular magnetic filtration, indicating its potential to improve the safety and effectiveness of HCC treatment.
Nanoparticles represent a major advancement in drug delivery, enhancing stability, solubility, and targeted delivery while reducing non-specific toxicity. Despite promising preclinical results, few nanoparticle platforms have successfully translated to clinical use due to limited pharmacokinetic (PK) data, off-target effects, manufacturing complexity, and a lack of long-term studies. Emphasizing the pivotal role of PK in this development process is essential for harnessing the full therapeutic potential of nanoparticle applications in clinical practice. In this review, we introduce the concept of model-informed nanoparticle development (MIND), an extension of model-informed drug development (MIDD) principles to nanomedicine that integrates knowledge of nanoparticle interactions with biological systems and state-of-the-art pharmacokinetic modeling to support evidence-based decision-making. Physiologically-based PK (PBPK) models simulate the absorption, distribution, metabolism, and elimination (ADME) of nanoparticles within the body, incorporating physiological parameters to predict their PK behavior. Population-based PK (PopPK) models utilize population variability to characterize nanoparticle PK across diverse patient groups, optimizing dosing strategies and personalized medicine approaches. Mechanistic models elucidate the intricate interactions between nanoparticles and biological systems, integrating cellular pathways and disease mechanisms to predict therapeutic outcomes and guide nanoparticle design. Through the MIND framework, these modeling approaches can enhance our understanding of nanoparticle PK, foster innovation in active agent delivery systems, and accelerate nanoparticle translation from research to clinical applications.
