Biomaterials Science最新文献

Engineering biomimetic extracellular matrices that isolate specific biochemical cues is essential for understanding how matrix chemistry regulates tumor cell behavior and therapeutic response. Aberrant sulfation due to proteoglycan expression is a hallmark of lung tumor matrices, yet its functional impact is difficult to study using conventional materials where mechanical and biochemical variables are coupled. To address this, mechanically matched sulfated alginate hydrogels are engineered to mimic the elevated sulfated glycosaminoglycan (sGAG) content of malignant ECM, enabling sulfation to be examined as a single, tunable variable. Within this system, ECM sulfation is shown to enhance tumor cell proliferation, promote oxidative and mitochondrial stress tolerance, suppress apoptotic signaling and attenuate the efficacy of cisplatin, gemcitabine and paclitaxel. Sulfated matrices preserve mitochondrial membrane potential, limit ROS accumulation, shift apoptotic gene expression toward a survival-favoring profile, selectively upregulate ABCB1-mediated efflux and modulate drug response through the PI3K/Akt-ABCB1 signaling axis. Functional inhibition of PI3K and ABCB1 uncovers drug-specific dependencies, while dual pathway targeting completely restores chemotherapeutic sensitivity. These findings identify ECM sulfation as a potent regulator of stress adaptation and therapeutic efficacy in lung adenocarcinoma and underscore the importance of biomimetic ECM design in controlling tumor cell fate and drug response.

The clinical translation of polymeric microneedle (MN)-based delivery systems for fibrotic diseases remains largely unexplored despite extensive preclinical advances. The dense extracellular matrix of pathological scars constitutes a formidable biophysical barrier that limits homogeneous macromolecular permeation. Here, we conducted a prospective, single-center, open-label, single-arm study evaluating a 12-week protocol combining microplasma radiofrequency (RF), poly(L-lactic acid) (PLLA) MNs, and topical milk-derived bioactive nanovesicles (mBNVs) in 26 patients with hypertrophic scars. Clinical scales and multimodal imaging were used to assess treatment-associated changes. At week 12, the combined protocol was associated with reductions in VSS and POSAS Patient Scale scores, scar stiffness and thickness, and dermoscopic vascular and pigmentation densities. MN-induced microchannels underwent rapid closure, treatment-related reactions were mild and transient, and no serious or systemic adverse events were observed. Collectively, these findings support the short-term feasibility, tolerability, and preliminary clinical activity of the combined protocol, offering a safe and non-steroidal paradigm for mechanically resistant pathological tissues.

Zwitterionic hydrogel coatings comprise three-dimensional networks of zwitterionic polymers that bear balanced anionic and cationic groups. These coatings exhibit superior hydration capacity, high drug-loading efficiency, excellent biocompatibility, and remarkable salt resistance. As a result, they have demonstrated significant potential for antimicrobial biomedical applications, i.e., wound dressings, drug delivery, and modifications of medical catheters and implants. In particular, in the context of kidney disease-associated catheters, zwitterionic hydrogel coatings display dual antimicrobial mechanisms: bacterial-repelling and bactericidal effects. Special emphasis is placed on smart coatings, including pH-responsive degradation and drug release, charge-switchable zwitterionic monomer applications, and self-healing functionalities. However, the mechanical properties of zwitterionic hydrogel coatings remain suboptimal. This limitation has been effectively mitigated through strategies consisting of crosslinking optimization, monomer modification to create triazole-zwitterionic hydrogels, and the development of multiple crosslinked zwitterionic hydrogel networks. Additionally, this critical review provides a detailed introduction to recently developed versatile adhesion methods, such as mussel-inspired chemistry, interfacial interpenetration and polycation-reinforced surface bridging strategies, for achieving robust hydrogel integration of hydrogels on catheters. Finally, key prospects for advancing catheter coating design toward clinical translation are outlined.

Non-invasive tracking of natural killer (NK) cells remains a major challenge in cancer immunotherapy, limiting our understanding of their in vivo migration and persistence. Magnetic particle imaging (MPI) offers a quantitative, real-time method for visualizing labeled cells, yet optimal labeling protocols for NK cells have not been established. Here, we evaluate commercially available iron oxide nanoparticles (IONPs) for MPI labeling of both NK92MI cells and primary human NK cells. Labeled cells retained viability and cytotoxicity, including activity against three-dimensional tumor spheroids, and were detectable by MPI. To further examine imaging performance in a biologically relevant context, we employed mouse phantoms that recapitulate organ-specific signal distributions, enabling evaluation of quantification and liver spillover effects. We identify key tradeoffs between particle colloidal stability and per-cell iron content; specfically, VivoTrax and VivoTrax Plus provided higher MPI signal but required post-labeling purification, reducing cell recovery, whereas Synomag-D and Perimag were more stable and preserved cell yield despite lower signal intensity per cell. These results provide a framework for selecting nanoparticles that balance detection sensitivity, cell viability, and workflow practicality, advancing non-invasive NK cell tracking.

PEG has been commonly considered safe and is widely used in pharmaceutical and personal care products. Concerns about its safety arised in relation to studies demonstrating its accumulation in some organs of animals treated with very high PEG dosages (e.g., 200 mg per kg per week for up to 12 weeks). Although these dosages are substantially higher (200-100 000 times) than those of PEG-containing drugs, the concerns might still be valid for chronic therapies if the polymer is not cleared after the accumulation. In this study, in addition to investigate the phenomena of PEG accumulation/elimination and its effects on full blood count, plasma biochemistry and behavioral performance of treated animals, we also studied new hydrolysable PEGs (HyPEGs) for reducing PEG accumulation. HyPEGs contain a cleavable linker that, upon in vivo hydrolysis, lowers by half the size of the polymer. We here evaluated the in vitro effect of 20- and 40 kDa conventional PEGs on macrophages' phenotype in THP1 cells, and the potential in vivo toxicity, biodistribution, and vacuolation in liver, kidneys, spleen, choroid plexus, heart, and lungs of a small library of 20- and 40 kDa-conventional and hydrolysable PEGs, with both linear and branched structures, administered twice weekly for 12 weeks at the high dosage of 200 mg per kg per week followed by an 8-week washout period (no PEG administration). We demonstrated that PEG internalization by macrophages resulted in molecular weight-dependent cellular responses. In vivo, all PEGs accumulated in the liver, spleen, kidneys, and choroid plexus, and in general accumulation of HyPEGs was less evident. The 8-week washout period allowed for the clearance of most of the accumulated PEGs in all organs except for the kidneys, likely because the kidneys are the terminal organs for PEG elimination. Overall, all PEGs did not show any hematotoxicity by analyzing biochemical- and hematological-parameters. Cytoplasmic PEG-negative vacuoles were present in the choroid plexus, suggesting adaptive cellular responses, but no signs of neurotoxicity were observed. Our results indicate that, although the different PEGs elicited distinct macrophage responses in vitro, all hydrolysable PEGs showed limited tissue accumulation in vivo without signs of toxicity, highlighting their safety.

Complex maxillofacial bone anatomy compromises the efficacy of local anesthetics. This study develops an ultrasound (US)/reactive oxygen species (ROS) cascade-responsive polylactic-coglycolic acid (PLGA) nanoparticle system for enhanced dental infiltration anesthesia and perioperative pain management. The nanoparticles, which were surface-modified with alendronate (ALN) via an ROS-cleavable thioketal (TK) linker and coloaded with bupivacaine (BUPI) and perfluorohexane (PFH), enabled enhanced bone targeting and penetration. Under US stimulation, PFH undergoes a liquid-gas phase transition, generating ROS that cleave TK linkers, switching the system from a "bone-targeting" to a "bone-penetration" state. This cascade mechanism facilitates deep tissue penetration of local anesthetics for enhanced anesthesia while enabling a dual-phase release profile: rapid US-triggered BUPI release for intraoperative analgesia and sustained diffusion for postoperative pain management. In rat models of tooth extraction and pulp injury, the system demonstrated superior efficacy over conventional BUPI, significantly increasing drug concentrations in the mandibular bone and improving pain-related outcomes. Biocompatibility was confirmed via histology and serum biomarkers. By overcoming maxillofacial bone barriers and enabling responsive, biphasic drug release, this platform represents a promising strategy to address the limitations of current local anesthetics in dentistry, reducing local anesthesia failure rates and improving perioperative pain control.

Dry eye disease is a chronic inflammatory disorder of the ocular surface in which tear film instability and hyperosmolarity perpetuate a self-sustaining cycle of epithelial damage and inflammation; however, the therapeutic efficacy of topical cyclosporine A (CsA), a mainstay of treatment, is severely limited by rapid tear clearance and poor ocular bioavailability. Here, we developed a CsA-modified hyaluronic acid conjugate (HA-CsA) that spontaneously self-assembled into nanoparticles for topical DED therapy. HA-CsA nanomicelles (HCN) were synthesized through thiol-maleimide coupling and exhibited good dispersibility and stability in physiological media, with tear-compatible pH and osmolality. Under hyperosmotic stress, CD44 expression was upregulated in human corneal epithelial cells, and R6G-labeled HCN showed markedly enhanced cellular uptake compared with free R6G, indicating improved epithelial delivery. Functionally, HCN demonstrated greater cytocompatibility than free CsA and more effectively suppressed hyperosmotic stress-induced expression of IL-1β, IL-6, IL-8, TNF-α, and MMP-9. In a desiccating-stress mouse model of DED, topically administered HCN significantly improved corneal epithelial integrity, tear secretion and goblet cell survival while broadly attenuating inflammatory gene expression, macrophage activation and epithelial apoptosis, outperforming free cyclosporine A across all parameters. This conjugation-driven nanoplatform integrates tear film stabilization, targeted epithelial delivery and sustained local immunomodulation into a single, well-defined formulation, providing a promising translational strategy for interrupting the vicious inflammatory cycle that drives dry eye disease.

Radiotherapy (RT) is a mainstay of cancer treatment, yet its efficacy is limited by tumor hypoxia, elevated glutathione (GSH) levels, and a lack of tumor-specific radiosensitizers. Herein, we synthesized iridium-doped carbon dots (Ir-CDs) and further camouflaged them with 4T1 cancer cell membranes to construct a biomimetic nanoplatform (Ir-CDs@CM) integrating homologous targeting, multimodal imaging, and nanozyme-mediated properties for enhanced radiosensitization. The synthesized Ir-CDs exhibited a uniform size of ∼2.25 nm and good water dispersibility. After encapsulation with 4T1 cell membranes, Ir-CDs@CM showed an average hydrodynamic diameter of ∼181.9 nm and a zeta potential of -17.0 mV, along with excellent colloidal stability, low cytotoxicity, favorable biocompatibility, and homologous targeting capability. Functionally, Ir-CDs@CM enabled dual-mode fluorescence (FL) and computed tomography (CT) imaging. Moreover, Ir-CDs displayed three nanozyme activities: GSH-depletion activity (47.13% GSH depletion), catalase-like activity (O₂ generation up to 11.9 mg L^-1), and peroxidase-like activity (a 5.17-fold increase in reactive oxygen species (ROS) generation under X-ray irradiation). This nanozyme-mediated oxygen evolution and ROS generation reduced 4T1 cell viability from 83% to 45.69% under 6 Gy irradiation. In vivo, the nanoplatform achieved excellent tumor accumulation and therapeutic efficacy in subcutaneous tumor-bearing mice, suppressing tumor growth within 14 days. Body weight fluctuations remained below 5% with no hepatorenal toxicity or tissue damage, confirming excellent biosafety. This strategy integrates membrane camouflage with iridium-based nanozyme technology for targeted imaging, microenvironment modulation, and radiosensitization, opening new avenues for integrated tumor therapy and diagnosis.

Interleukin-12 (IL-12) potently activates antitumor immune responses and compensates for the challenge of insufficient T cell activation and infiltration faced in immune checkpoint therapy. However, its clinical application is limited by severe systemic toxicity and the upregulation of PD-L1 on tumor cells during treatment. Here, we developed iLAN_pTyr-IL-12, a lipid-assisted nanoparticle system loaded with tyrosinase (Tyr) promoter-driven IL-12 plasmids, designed to achieve specific and sustained IL-12 expression exclusively in melanoma cells. The secreted IL-12 promoted dendritic cell maturation, T cell activation and proliferation, and IFN-γ secretion. Notably, iLAN_pTyr-IL-12 treatment upregulated PD-L1 expression on tumor cells, suggesting a negative feedback loop that supports the rationale for combination with anti-PD-L1 (αPD-L1). In a subcutaneous B16-F10 melanoma model, iLAN_pTyr-IL-12 monotherapy significantly enhanced tumor suppression and increased intratumoral infiltration of T cells and NKT cells, along with a decreased M2/M1 macrophage ratio. When combined with αPD-L1, it produced an enhanced antitumor effect, achieved a tumor growth inhibition rate of 83% and further augmented intratumoral CD8⁺ T cell infiltration. Additionally, no significant systemic toxicity or organ damage was observed. Collectively, these findings demonstrate that iLAN_pTyr-IL-12 enables tumor-specific IL-12 expression and, when combined with αPD-L1, provides a promising cytokine-immune checkpoint combination immunotherapy with reduced off-target toxicity.

Metal oxide nanoparticles (NPs) coupled with dissimilatory metal-reducing bacteria enable continuous redox cycling through extracellular electron transfer (ET), a process central to bioremediation and bioenergy applications. However, the molecular mechanisms governing ET at the outer membrane-iron oxide NP interface remain unclear. Here, atomistic molecular dynamics simulations were employed to elucidate how the extracellular cytochromes of Shewanella oneidensis cooperatively mediate iron oxide NP adsorption, a prerequisite for extracellular ET. Our study shows that MtrF and two OmcA decaheme cytochromes are asymmetrically associated through their N- and C-terminal regions with distinct interaction energies, and their terminal heme groups (heme 10) of the long chains in the staggered cross-heme networks are connected to form a continuous heme network. This assembly sterically occludes MtrF heme 10 and redirects NP adsorption to alternative termini of the cross-heme network, including heme 5 (the opposite end of the long heme chain), where MtrF mediates binding through electrostatic interactions involving its heme groups and surface residues. NP adsorption also occurs near heme 2 at the terminus of the MtrF short heme chain, where OmcA residues primarily stabilize NP attachment. These results identify MtrF as the primary mediator of extracellular ET and establish OmcA as an interfacial stabilizer that enhances NP binding without directly mediating ET.