ACS Publications最新文献

The mechanical properties of the extracellular matrix play a key role in regulating cellular functions, yet many in vitro models lack the mechanical complexity of native tissues. Traditional hydrogel-based substrates offer tunable stiffness but are often limited by instability, porosity, and coupled changes in both mechanical and structural properties, making it difficult to isolate the effects of stiffness alone. Here, we introduce a spatially patterned dual-cure polydimethylsiloxane (DC-PDMS) system, a nonporous, mechanically tunable polymer that allows for precise spatial control of stiffness over a range of patho-physiological values. This platform enables the design and creation of in vitro models for studying the influence of spatial mechanical cues on cellular behavior. To demonstrate its utility, we examined primary cardiac fibroblast responses across different substrate stiffness conditions. Fibroblasts on soft regions exhibited rounded morphologies with disorganized actin networks, while those on stiffer regions became more elongated with highly aligned stress fibers, indicating stiffness-dependent cytoskeletal remodeling. Stiff substrates also led to nuclear compression and increased nucleus curvature, correlating with increased nuclear localization of YAP, a key mechanotransduction regulator. By allowing cells to interact with mechanically distinct regions within a single substrate, this system provides a powerful approach for investigating mechanotransduction processes relevant to fibrosis and other mechanically regulated diseases. The ability to create stiffness patterns with subcellular resolution makes DC-PDMS a valuable tool for studying cell-material interactions, enabling new insights into mechanobiology-driven cellular responses and therapeutic targets.

Hydrogels show great potential for mimicking human weight-bearing tissues due to their extremely high water content and desirable behavior, including softness and elasticity. However, developing joint cartilage-mimicking hydrogels with both superior mechanical properties and stable lubrication remains challenging. This study presents a self-assembled heterostructure hydrogel approach. A mechanically robust hydrogel with sustained lubrication properties is achieved by incorporating a hydrophilic network into a hydrophobic polyethyl acrylate (PEA) matrix. Two polymer networks interweave at the microstructural level, generating water-rich and water-poor phases. Outstanding load-bearing capacity is achieved by the flexible hydrophilic polymer network efficiently dispersing impact stress into the rigid hydrophobic network. Meanwhile, a hydrated lubricating layer forms on the hydrophilic network's surface, ensuring sustained lubrication. Moreover, the hydrophobic PEA network incorporation limits swelling in the hydrophilic network, imparting exceptionally stable antiswelling properties to the hydrogel. This study demonstrates that the heterostructure hydrogel maintains stable mechanical properties in aqueous solutions while providing lubricity, offering a novel approach to developing biomimetic materials with mechanical robustness and sustained lubricity.

Finasteride is widely used to treat androgenetic alopecia; however, concerns regarding systemic side effects limit its long-term use. Here, we developed a peptide-based, carrier-free topical delivery system that enhances hair growth while minimizing systemic exposure to finasteride. The system employs a skin- and cell-penetrating peptide with intrinsic anti-inflammatory activity as both the delivery vehicle and a therapeutic component. Upon coassembly with finasteride via a compositionally tuned hydrophobic block, the peptide formed well-defined nanocomplexes (NCs) that synergistically improved dermal papilla cell viability. In vivo, the NCs promoted hair regeneration to a level comparable to, or exceeding, that of 5% minoxidil, despite delivering approximately 40-fold less finasteride than the standard oral dose. Biochemical analyses confirmed accelerated transition of hair follicles from the catagen to anagen phase. This topical carrier-free strategy enhances finasteride efficacy while reducing side effects and offers a versatile platform for dermatological drug delivery.

Cell-ECM communication plays a critical role in the correct tissue development, disease progression, and therapeutic outcomes. The interest in controlling the mechanical properties of the ECM-mimetic systems has changed from the classical concept of elastic networks to mimic the viscoelastic behavior of the native tissue. Recently, the use of supramolecular chemistry has emerged as a promising strategy to achieve this behavior. In this work, alginate-based hydrogels were developed with a dual cross-linking system comprising dynamic cucurbit[8]uril host-guest homoternary complexes and covalent photo-cross-linking of methacrylate groups. By adjusting the ratio of covalent to dynamic bonds, control over the stress relaxation time scale was achieved, which offers an entry to mimic the viscoelastic properties of native soft tissues. Furthermore, this hydrogel formulation was found to be noncytotoxic and promotes cell survival, attachment, and alignment.

Cancer stem cells (CSCs) are a subpopulation of tumor cells with strong tumorigenic ability and high resistance to conventional therapeutic strategies due to the protected niche and poor drug penetration. While self-assembled nanosystems based on small-molecule self-assembly show therapeutic promise, limitations such as low targeting and unstable drug release still constrain their applications. In this study, we developed CD44-targeted RHID (ICG-DOX@RA-HA-DOX) nanocomplexes with a shell of hyaluronic acid-retinoic acid-doxorubicin (RA-HA-DOX) conjugates and a core of DOX-indocyanine green (ICG), which exhibited sustained and pH-responsive release properties. The released DOX and ICG could synergistically eliminate bulk tumors via chemotherapy and photothermal therapy. Concurrently, the released RA could promote CSC differentiation, further reducing stemness, self-renewal, and mammosphere formation, thereby enhancing the therapeutic sensitivity of CSCs to combined therapy. This integrated photothermal-differentiation-chemotherapy approach demonstrated strong antitumor efficacy both in vitro and in vivo, providing a promising nanotherapeutic strategy against CSC-driven malignancies.

Targeted delivery of therapeutics to bladder cancer is crucial for optimizing therapeutic efficacy and minimizing side effects. In this study, a novel targeted nanocarrier system was developed to enhance bladder cancer targeted therapy by modifying liposomes with 4-carboxyphenylboronic acid (CPBA), enabling selective binding with sialic acid residues overexpressed on bladder cancer cells. To further improve therapeutic outcomes, we employed a combination therapy based on chemotherapy and immunotherapy to both eliminate tumor cells and activate antitumor immune responses. We fabricated tumor-targeting liposome-chitosan-CPBA (LPCB) nanoparticles coloaded with doxorubicin (Dox), a chemotherapeutic agent, and resiquimod (R848), a toll-like receptor (TLR) 7/8 agonist that stimulates antitumor immunity. LPCB nanoparticles encapsulating Dox and R848 (LPCBDR) demonstrated enhanced binding to bladder tumor cells (T24, MB49) and cytotoxicity compared to nontargeted (non-CPBA incorporated) nanoparticles. LPCBDR nanoparticles also showed enhanced activation of murine dendritic cell (DC) populations characterized by the upregulation of costimulatory molecules. In vivo biodistribution studies with Cy7-labeled nanoparticles confirmed preferential tumor accumulation of LPCB NPs compared to nontargeted nanoparticles. Therapeutic efficacy using MB49 subcutaneous tumor model revealed that LPCBDR treatment group significantly reduces tumor volume compared to nontargeted nanoparticles and free drugs. Flow cytometric analysis of tumor and spleen samples further showed robust activation of Natural Killer (NK) cells, CD4⁺ T cells, and CD8⁺ T cell effector functions. Combined results demonstrate that sialic acid targeting LPCBDR nanoparticles offers a promising drug delivery platform for bladder cancer therapy.

To investigate the ability of novel Gyroid-shaped titanium alloy (TC4) porous bioscaffolds to induce angiogenesis and osteogenesis in bone defect areas. This study employed selective laser melting (SLM) technology to fabricate Gyroid shaped and Cube-shaped TC4 porous bioscaffolds, using the commonly used cube shape as a control. The unit cell size was 4 mm, with a wall thickness or rod diameter of 300 μm and a porosity of approximately 80%. These scaffolds were implanted into rabbit mandibular defect sites (10 mm × 7 mm × 5 mm) to evaluate the angiogenic and osteogenic potential of the Gyroid-shaped scaffold. Material characterization revealed that sandblasted and acid-etched (SLA) TC4 scaffolds met design specifications, exhibiting uniformly distributed micrometer-scale pores and enhanced surface hydrophilicity. Histological staining revealed that compared to the Cube-shaped scaffold, the Gyroid-shaped scaffold induced greater angiogenesis and new bone formation within the bone defect area. Both scaffolds demonstrated good biocompatibility. Western Blot and RT-qPCR results indicated that the Gyroid-shaped scaffold possessed superior angiogenesis potential (compared to the Cube-shaped scaffold). During the early implantation phase (1-2 weeks), Gyroid-shaped scaffolds exhibited higher expression of platelet-endothelial cell surface adhesion molecule 1 (CD31) and endothelial mucin (EMCN). Concurrently, vessel distribution within the scaffold showed spatial variation. Additionally, gene expression of hypoxia-inducible factor 1α (HIF-1α) and vascular endothelial growth factor A (VEGFA) was elevated in the early bone defect area. Imaging analysis confirmed successful implantation of both scaffolds, with the Gyroid-shaped scaffold exhibiting a higher proportion of new bone formation. Consequently, the novel Gyroid-shaped TC4 porous bioscaffold demonstrates excellent potential for angiogenesis and osteogenesis, providing a reference for Gyroid-shaped scaffold-based bone defect repair.

Chemo-immunotherapy has been an emerging synergistic strategy for melanoma treatment. However, major challenges still remain, including side effects of chemotherapeutic agents and insufficient efficacy of immunotherapy. In the present work, we designed a thermosensitive polypeptide hydrogel-based drug delivery system to achieve the codelivery of doxorubicin (DOX) and a Toll-like receptor (TLR)-9 agonist, CpG. The hydrogel system was engineered by incorporating cancer cell membrane enveloped hollow mesoporous silica loaded with DOX and the mPEG-ss-PEI/CpG nanocomplex, resulting in an enhanced therapeutic effect. Drug-loaded hydrogel system exhibited sustained drug release, enhanced immune cell activation, and induction of immunogenic cell death (ICD) of tumor cells. In vivo antitumor studies revealed that the drug-loaded hydrogel effectively inhibited tumor growth, and promoted expansion of CD8⁺ T cells and maturation of dendritic cells (DCs), facilitating favorable modulation of the tumor microenvironment. Hence, the developed drug-loaded hydrogel system has considerable potential as a platform for combinatorial chemo-immunotherapy in melanoma treatment.

Nanoscale wear particles generated over time in the implant-bone interface induce profound periprosthetic inflammatory osteolysis, the most common complication after total joint arthroplasty, while macrophages serve as key initiators of this response. Ferroptosis represents a recently identified mode of regulated cell death distinguished by its nonapoptotic nature and reliance on iron-driven lipid peroxidation, which is strongly linked to inflammatory processes within macrophages. However, the contribution of macrophage ferroptosis to the development of wear particle-induced periprosthetic osteolysis has not yet been elucidated. Here, we revealed the existence of macrophage ferroptosis in both the soft tissue from the implant-bone interface of patients with aseptic loosening and wear-particle-stimulated BMDMs, which promoted inflammatory osteolysis. Our results further suggested that wear particle-induced macrophage ferroptosis is mainly associated with GPX4-related antioxidized function impairment rather than iron metabolism alteration. Mechanistically, we found that wear particle-induced macrophage ferroptosis was mediated by inhibition of the Sirtuin 1/Nrf2/GPX4 pathway, while activation of this pathway effectively alleviates the wear particle-related periprosthetic inflammatory osteolysis. Overall, our results uncovered that wear particles drive macrophage ferroptosis via inhibiting the Sirtuin 1/NRF2/GPX4 pathway to induce periprosthetic inflammatory osteolysis and provide new insights into the intricate cellular and molecular mechanisms responsible for aseptic implant loosening.

Extrusion-based bioprinting enables precise spatial control over bioink deposition and offers the advantages of cost-effectiveness, versatility, and biocompatibility. While extensive research has focused on assessing bioink printability and developing printing techniques, limited attention has been directed toward the interplay among material properties, structural design, and process optimization. In this study, the relationships among the rheological behavior of the hydrogel, structural characteristics of models, and planning strategies of the path were systematically investigated. The printability of low- and high-viscosity hydrogels was evaluated through the fabrication of pattern arrays and three-dimensional (3D) grid constructs. Results indicated that low-viscosity hydrogels were more suitable for patterns involving frequent extrusion state transitions, whereas high-viscosity hydrogels facilitated steady-state, long-duration printing of three-dimensional scaffolds. To further explore structure-specific path planning, a perfusable chip comprising flat, support, wall, and overhanging features was designed and printed. To address the inherent limitations of conventional 3-axis bioprinting in fabricating large-scale unsupported overhangs, the printing path was optimized according to the rheological properties of hydrogels. Using this strategy, a 10 × 10 mm² overhanging structure was successfully fabricated, and perfusable hydrogel chips with tunable fluid flow were produced. The chips exhibited reliable flow performance and sealing capacity with a maximum burst pressure of 1.2 kPa. Collectively, this work presents a design framework that integrates material properties with structural features to optimize path planning and printing processes, offering valuable insights for the construction of advanced 3D cell culture systems via extrusion-based bioprinting.