ABSTRACT Osteoarthritis (OA) progression is closely associated with the deterioration of joint lubrication. Although surface‐grafted lubrication coatings can reduce friction, they are susceptible to mechanical damage under repetitive shear stress, resulting in rapid lubrication failure. Therefore, constructing a dynamically reconfigurable lubrication interface capable of continuous restoration under friction is critical for long‐term joint protection. Herein, a dynamically self‐repairing hydration lubrication microsphere system (HMs‐CD@Ad‐PMPC) is developed based on host–guest interactions. β ‐Cyclodextrin ( β ‐CD)‐functionalized silk fibroin microspheres dynamically recruit adamantane (Ad)‐terminated poly(2‐methacryloyloxyethyl phosphorylcholine) (PMPC) brushes through supramolecular host–guest recognition, thereby establishing a robust yet reversible hydration lubrication interface. Under shear stress during joint motion, partial dissociation of Ad‐PMPC chains induces transient lubrication attenuation, while spontaneous molecular reassembly rapidly restores the lubrication interface upon stress release, thereby enabling dynamic self‐repairing lubrication. In vitro, HMs‐CD@Ad‐PMPC maintains a stable low coefficient of friction (COF, 0.03–0.04) under cyclic shear conditions, exhibiting excellent wear resistance and long‐term lubrication stability. In vivo, the system effectively reduces joint wear, preserves cartilage integrity, and significantly delays OA progression. This work establishes a dynamic lubrication strategy capable of restoring interfacial functionality under mechanical stress, providing a promising platform for long‐term joint lubrication and OA therapy.
ABSTRACT Osteoarthritis (OA) involves alterations in cartilage mechanics, matrix composition, and mineralization, yet in vitro models that resolve remodeling transitions remain limited. Scaffold‐free cartilage microtissues derived from human dental pulp stem cells (hDPSCs) are subjected to sequential dynamic rocking culture and triiodothyronine (T3) treatment. Dynamic rocking produces superficial Col I‐positive fibrotic and matrix‐degrading changes, whereas T3 induces proteoglycan loss, increased Col I and MMP13, irregular mineral deposition, and altered nanomechanical properties, defining a mixed terminal catabolic and mineralizing OA‐like state. Transcriptomic profiling shows stage‐associated reorganization rather than uniform pathway activation. In T3‐treated microtissues, ATF6‐associated ER‐stress abnormalities include ER cisternal dilation and increased ATF6 signal. Targeted ATF6 knockdown reduces ATF6 signal, ER dilation, extracellular‐matrix disorganization, and ER‐stress/proteostasis and inflammatory/catabolic transcriptional module scores, supporting ATF6‐associated signaling as a functionally relevant component of this degenerative state. In mouse temporomandibular joint and knee OA models, intra‐articular Ad‐shATF6 is associated with partial cartilage preservation and subchondral‐bone indices shifted toward control ranges.
ABSTRACT Mature adipocytes within the breast tumour microenvironment contribute a significant role in malignant progression. At the invasive front of breast tumours, mature adipocytes undergo morphological and phenotypic changes and may provide metabolic support to fuel tumour growth and spread. However, investigations into mature adipocyte—breast cancer interactions have been limited by the lack of suitable in vitro models. Here, we developed an innovative 3D in vitro co‐culture system allowing direct contact between patient‐derived mature breast adipocytes and breast cancer cell lines, to systematically examine cell‐cell interactions over 21 days. In co‐culture with triple negative breast cancer cells (MDA‐MB‐231), mature adipocytes exhibited loss of Perilipin 1 (PLIN1) expression and were associated with reduced chemotherapy responsiveness and increased Major Vault Protein (MVP) abundance. In contrast, Luminal A (MCF7) breast cancer cells displayed increased expression of mesenchymal markers (N‐cadherin and Vimentin), consistent with a partial epithelial to mesenchymal transition. The direct 3D co‐culture model developed by this work provides a novel platform to study breast cancer subtype‐specific interactions between mature adipocytes and cancer cells, revealing interactions associated with chemotherapy responsiveness and malignant progression.
ABSTRACT Stem cell‐based therapy holds promise for endometrial regeneration but suffers from rapid cell loss in the oxidative and cytokine‐deficient uterine niche. We developed a biomimetic decellularized extracellular matrix integrated with platelet‐rich plasma (ECM/PRP) that serves as a bioactive cytokine reservoir designed to construct a supportive local microenvironment capable of retaining cytokines and maintaining transplanted cell viability. The ECM binds PRP‐derived cytokines, stabilizing their bioactivity and converting burst release into sustained signaling. Adhered human umbilical cord mesenchymal stem cells (HUC‐MSCs) respond to these anchored cues, with changes in mitochondrial electron transport activity correlating with enhanced cellular antioxidant capacity. This ECM/PRP composite improves HUC‐MSC survival, alleviating intracellular ROS, sustain their paracrine secretion under the IUA pathological microenvironment, and elevate the number of surviving transplanted HUC‐MSCs in vivo. In a murine intrauterine adhesion (IUA) model, MSC@ECM/PRP enhanced endometrial proliferation and microvessel density while reducing collagen deposition. These coordinated changes facilitate reconstruction of physiological endometrial structure and produce a marked improvement in fertility relative to the untreated IUA group. Collectively, the adaptive MSC@ECM/PRP scaffold protects transplanted HUC‐MSCs against oxidative stress in the IUA microenvironment, facilitates endometrial structural repair and angiogenesis, suppresses excessive fibrosis, and achieves satisfactory therapeutic and fertility‐restoring effects in IUA.
ABSTRACT Hyperlipidemia is a systemic metabolic disorder closely associated with chronic inflammation. Effective management requires integrated strategies that simultaneously lower lipid level and attenuate inflammation. Nucleic acid therapeutics, such as proprotein convertase subtilisin/kexin type 9 (PCSK9) siRNA, represent a breakthrough in lipid‐lowering therapy. However, they either lack direct anti‐inflammatory effects (GalNAc‐siRNA) or are prone to triggering unintended inflammatory responses themselves such as lipid nanoparticles (LNPs). Milk‐derived extracellular vesicles (MDEs) emerge as naturally anti‐inflammatory nanocarriers that suppress key pro‐inflammatory cytokines by 30.0%–96.5% in vitro. However, MDEs predominantly undergo endocytic trafficking with substantial endosomal/lysosomal sequestration, which can limit productive cytosolic siRNA delivery. To address this, we developed engineered MDEs by incorporating 30.0% ( w/w ) probiotic‐derived glycolipids into their membranes to facilitate early endosomal escape. When loaded with PCSK9 siRNA, the engineered MDEs achieved a remarkable silencing efficiency of 90.2 ± 0.2%, significantly outperforming both unmodified MDEs and conventional LNPs. In hyperlipidemic mice, systemic administration of engineered MDEs improved serum lipid profiles, reduced lipid accumulation and systemic inflammation, and showed a favorable safety profile under the conditions examined. Collectively, this work provides a promising nucleic acid delivery platform based on engineered MDEs for enhanced hyperlipidemia therapy through simultaneous lipid‐lowering and anti‐inflammatory effects.
