To enable Small Interfering RNA (siRNA) transdermal delivery, we use computational modeling to predict key properties of four cationic peptide carriers. These parameters can be utilized for the prediction of peptide carrier diffusion within the stratum corneum, thereby facilitating the screening of carriers with transdermal delivery capabilities. We take this opportunity to examine the discrepancy between computer-simulated transdermal vehicle functions and actual therapeutic efficacy. We validate the therapeutic efficacy of four peptide carriers by employing both human cell-derived 3D skin models and a murine psoriasis model. To advance clinical applications, we developed a skin-adhesive spray that contains peptide carriers loaded with ADAM17-targeting siRNA. Following penetration into the dermis, the siRNA-loaded carriers are internalized by immune cells, downregulating a disintegrin and metalloproteinase 17 (ADAM17) protein expression. This consequently suppresses Tumor Necrosis Factor-α (TNF-α)-mediated inflammatory responses and ameliorates psoriatic pathology. Finally, by employing multiplex immunofluorescence imaging to visualize the spatial proximity between epithelial and immune cells, we elucidate their functional cross-talk within the tissue microenvironment. The findings demonstrate that our computer-optimized peptide carrier achieves transdermal siRNA delivery and reprograms the psoriasis-associated inflammatory microenvironment.

The treatment of severe bone defects remains a critical clinical challenge. The primary factor underlying impaired healing is the absence of periosteum and osteogenic blood vessels at the defect site. During the early stages of bone regeneration, elevated levels of reactive oxygen species (ROS) are commonly observed, which harms mitochondrial function and osteogenic effect. Here, we developed a microenvironment-responsive trilayered bionic periosteum (NMC@POB) designed to sequentially promote bone regeneration via osteogenic-angiogenic coupling. This construct features an outer layer of collagen embedded with tannic acid-cerium nanozymes (TA-Ce NMs) to scavenge ROS and restore redox homeostasis, a middle polylactic acid (PLA) layer for structural support, and an inner core of oxidized xyloglucan-loaded bone morphogenetic protein-2 (OXG-BMP2) to provide sustained osteo-inductive cues. In vitro and in vivo evaluations demonstrated that NMC@POB effectively reduced oxidative stress, enhanced mitochondrial function, and promoted coordinated osteogenesis and angiogenesis in a rat calvarial defect model. Transcriptomic analysis further revealed significant activation of the Wnt/β-catenin pathway, contributing to the upregulation of genes involved in both bone formation and neovascularization. Collectively, this trilayered periosteum offers a bionic and microenvironment-responsive strategy for orchestrated bone regeneration in challenging defect.

Tissue fibrosis following injury often leads to severe complications in humans. Recent research highlights that macrophage hypermigration and activation play a critical role in fibrosis development. Emerging evidence suggests that macrophage sensing of tissue injury via damage-associated molecular patterns (DAMPs) is crucial for their migration and activation. Excessive injury sensing is linked to macrophage hyperactivity, aberrant inflammation, and fibrosis. Recent studies have shown that polyinosinic acid (Poly I) can reduce macrophage activation by inhibiting signaling pathway associated with macrophage scavenger receptors (MSR). Based on this, we developed an electrospun polycaprolactone (PCL) fibrous membrane incorporating Poly I (PCL-Poly I) to ensure its early sustained release and function as an effective physical barrier. In vitro and in vivo results showed that Poly I could mask macrophage early injury sensing by downregulating MSR1/PI3K/AKT/SPP1 pathway. The local implantation of PCL-Poly I could reduce the early aggregation and activation of macrophages in the epidural fibrosis (EF) zone, thus suppressing the fibroblast activation and EF progress, with its therapeutic efficacy lasting up to 8 weeks after laminectomy. In conclusion, this study demonstrates the potential of biomaterial-based strategies to modulate immune responses, offering a novel upstream solution for treating fibrosis-related conditions.

Perioperative neurocognitive disorder (PND) is a common complication in older surgical patients, leading to increased neurodegenerative and death risk, augment socioeconomic burdens. Despite its prevalence, the reasons of why this complication occurs highly in older, underlying pathogenesis mechanisms, and effective treatments remain unclear. Senescence associated secretory phenotype (SASP), resulting from cellular senescence, drives inflammaging and cognitive decline. However, the association between cellular senescent and poor cognitive outcome is seldomly defined in PND. Herein, we showed that anesthesia and surgery in aged mice further increase hippocampal neuron senescent burden, manifest as increased senescence-like markers (CDKN2A/p16, CDKN1A/p21, SASP, SA-β-Gal), along with lipofuscin and lipid droplet accumulation and synaptic dysfunction. We identified elevated PF4, a platelet-derived factor, as a defensive response in older PND mice. Intraperitoneal PF4 administration mitigated neuronal senescence burden and improved cognitive dysfunction. Considering the older, frail patients and shorter perioperative period, we developed microfluidic hydrogel microspheres and cationic thermosensitive hydrogel complexes for nasal PF4 delivery enabling satisfy minimally invasive, less frequent dosing and sustained treatment. These findings reveal a critical role for cellular senescence in PND and propose PF4-based therapies as a promising translational strategy.

Small interfering RNAs (siRNAs) have brought revolutionary advances as promising therapeutic candidates for ulcerative colitis, owing to the durable anti-inflammatory efficacy and favorable biocompatibility. Nevertheless, the clinical translation of oral siRNA therapeutics remains hindered by the harsh conditions of the gastrointestinal tract. Thus, a colon-specific modular hydrogel platform (IG@SP@FK LNPs@siTNFα) was engineered through integration of microalgal biotechnology and nanomedicines. The system comprised three functionally components: (i) a cathepsin B/glutathione (GSH) dual-responsive gemini-like cationic MA-FK-SS lipid nanoparticles core encapsulating tumor necrosis factor-α siRNA (FK LNPs@siTNFα); (ii) a negatively charged Spirulina (SP) intermediate layer (SP@FK LNPs@siTNFα); and (iii) an outer inulin-derived hydrogel (IG) coating. The IG layer provided robust protection against harsh gastrointestinal conditions and regulated the gut microbiota homeostasis. Subsequent colonic degradation of IG triggered site-specific release of SP@FK LNPs@siTNFα, which exhibited enhanced mucosal adhesion through the intrinsic helical architecture of SP. Notably, FK LNPs@siTNFα demonstrated efficient cellular internalization, proton-sponge effect-driven endosomal escape and dual-responsive siRNA release, ultimately silencing the expression of TNF-α. IG@SP@FK LNPs@siTNFα significantly attenuated the progression of ulcerative colitis via suppression of pro-inflammatory cytokine cascades (IL-6, IL-1β, TNF-α), restoration of intestinal barrier integrity, and normalization of gut microbiota homeostasis. This nano-biohybrid system established a paradigm for oral nucleic acid delivery, combining spatiotemporal control and multi-mechanistic intervention for precise gene therapy of ulcerative colitis.

Anisometric rod-shaped microgels are promising building blocks for tissue engineering, offering injectability, porosity, macroscopic anisotropy, and biochemical functionality-key features for directing cell adhesion, growth, alignment, and interaction. The continuous production of thin or highly porous elongated microgels is therefore desirable, preferably offering control over their stiffness, size, and aspect ratio. We present advancements in compartmentalized jet polymerization, a microfluidic technique that generates microgels that are ten times narrower than the channel width by forming a polymer jet and crosslinking alternating segments with a pulsed laser. Originally limited to diameters of ∼8 μm, we have now refined the method to produce microgels as small as ∼3 μm. Additionally, we developed ultra-soft and ultra-porous microgels that swell to diameters of 50-120 μm with pore sizes in the range 2-5 μm. While the thin soft microgels can be employed in our Anisogel technology to combine injectability with magnetic alignment, the ultra-porous microgels would increase diffusion in our microporous annealed particle (MAP) scaffolds made from rod-shaped microgels. This paper focuses on the continuous production and characterization of rod microgels with properties that cannot be achieve with other methods. Furthermore, we report initial results of the microgels' potential and challenges to be used inside an Anisogel, which was so far only possible with stiffer magneto-responsive microgels produced by an in-mold polymerization batch process, and to form MAPs by cell-induced assembly of the ultra-porous rods. Further studies will be required to fully exploit the potential of these unique microgels for tissue engineering applications.

Artificial blood vessels are commonly used to treat vascular damage and diseases. While large-diameter artificial blood vessels have been widely used in clinical practice, small-diameter artificial blood vessels (<6 mm) face significant challenges, including acute thrombosis in the short-term and intimal hyperplasia in the long-term. In this study, mesenchymal stem cells overexpressing Gremlin1 (Gremlin1-MSCs) were implanted as seed cells on the inner layer of polyurethane (PU) small-diameter artificial blood vessels fabricated by electrospinning technology. Additionally, the adhesion of Gremlin1-MSCs was enhanced by coating the lumen surface of the vessels with polydopamine (PDA). This approach aimed to promote endothelialization, thus reducing the risks of acute thrombosis and intimal hyperplasia. The in vitro results demonstrated that Gremlin1-MSCs retained their MSC characteristics and possessed the ability to inhibit monocyte proliferation and macrophage polarization. Furthermore, the PDA-coated PU small-diameter artificial blood vessels exhibited excellent biocompatibility and hemocompatibility. After implantation in rabbit carotid arteries, Gremlin1-MSCs significantly improved the long-term patency of small-diameter artificial blood vessels and reduced intimal hyperplasia of natural blood vessels at the suture site compared to the control MSCs (Ctrl-MSCs) or no MSCs treatment. This study provides a promising approach to improve the patency of small-diameter artificial blood vessels and highlights the potential of Gremlin1-MSCs as effective seed cells for this application.

The clinical utility of PEGylated nanomedicines is constrained by anti-polyethylene glycol (PEG) immunity, which drives accelerated blood clearance and infusion reactions. We address this by rationally tuning polymer architecture: a short-chain, high-density PEG brush (PEG500) grafted onto rigid mesoporous silica nanoparticles (MSNs). This design limits immune recognition through three synergistic features: (i) shortened PEG chains reduce epitope accessibility, (ii) high grafting density (4.43 chains/nm) provides a strong steric barrier, and (iii) the rigid silica surface minimizes PEG backfolding/burial. At equivalent PEG concentrations, ELISAs revealed near-background binding of anti-PEG IgG (6.3) and IgM (AGP3) to MSN-PEG500, in sharp contrast to the strong recognition of PEG2000-based Lipodox. Antibody binding scaled with chain length (PEG2000 > PEG1000 > PEG500), consistent with increased epitope exposure on longer chains, while the compact PEG500 brush on MSNs largely abrogated detection. In vivo, radiolabeled MSN-PEG500 showed prolonged circulation and up to 25 %ID/g tumor uptake at 24 h. In robustly anti-PEG-immunized mice, doxorubicin-loaded MSN-PEG500 preserved antitumor efficacy with 100 % survival, whereas Lipodox (PEG2000) induced fatal hypersensitivity. Mechanistic studies implicated complement activation in PEG2000-associated immunotoxicity; C3 blockade with compstatin attenuated hypothermia (median ΔT reduced from ∼10 °C to ∼2 °C) in sensitized hosts. These findings indicate that nanoscale control of PEG conformation governs immune recognition and safety, offering a clinically tractable blueprint for engineering immune-evasive nanotherapeutics.

The use of macrophage cell therapies is limited by their tendency to change phenotype in response to external cues in situ. Here we demonstrate that an optimized lipid nanoparticle (LNP) formulation effectively delivers IL4 mRNA to human and murine primary macrophages, resulting in rapid transfection, IL-4 secretion, and reparative phenotype modulation. In a model of murine volumetric muscle loss, adoptively transferred macrophages pre-treated with IL4-LNPs maintained a reparative phenotype for at least one week, despite the inflammatory injury microenvironment. IL4-LNP-treated macrophages also promoted a reparative phenotype in endogenous macrophages and supported muscle repair outcomes, including increased vascularization, fiber size distribution, and remodeling of the scaffold. T cell subtype in the muscle or the draining lymph node was not affected. The novel strategy established here may facilitate the control and use of macrophage cell therapies for other applications in regenerative medicine.

The heparan sulphate proteoglycan, Glypican-4 (GPC-4), is an integral component of cell surfaces that fulfils key functions as a modulator of cell communication. Over time, human GPC-4 (hGPC4) has gained recognition as a valuable target for enhancing the therapeutic potential of human pluripotent stem cells (hPSCs). hGPC-4 is also a promising diagnostic and therapeutic target for a range of developmental and neurological disorders, as well as cancer. Its involvement in multiple biological processes and its impact on cellular signaling pathways make it a compelling candidate for future research and clinical applications. Here, we report RB1 and RB3 as the first hGPC-4-specific nanobodies. Both RB3 and RB1, bind recombinant hGPC4 with affinities in the tens of nanomolar range, whereas only RB1 recognizes native, cell-expressed hGPC4, highlighting its potential for functional studies. Notably, the bivalent nanobody Fc-fusion form of RB1, termed RB1-Fc, demonstrates a significant ∼14-fold increase in apparent binding affinity on cells when compared to the monovalent RB1. Furthermore, binding of RB1-Fc to hGPC-4 is dependent on the native conformation of hGPC-4, demonstrating that RB1-Fc is a conformational nanobody. Notably, RB1-Fc neutralizes the activity of GPC-4, as shown by our functional studies in hPSCs. These studies demonstrate the potent efficacy of the lead hGPC4 nanobodies, RB1-Fc and RB3. They also provide a solid rationale for using these nanobodies in the detection and characterization of physiologically and clinically relevant hGPC-4. Additionally, their potential as agents for therapeutic targeting of hGPC-4 opens new avenues for treating disorders associated with dysregulated hGPC-4 activity.

During early stages of development of cerebral organoids, budding neuroepithelia display striking changes in size and morphology, occurring very rapidly. Whilst mechanical forces mediated by cadherin-cadherin junctions are known to control the assembly, maturation and stability of epithelia, little is known of the mechanical context associated with neuroepithelial organoid development. In this report, we demonstrate a rapid translocation of YAP to budding neuroepithelial apical junctions, suggesting the build-up of strong compressive forces early on in their development. To study the mechanics of budding rosettes, we designed oil microdroplets stabilised by protein nanosheets displaying cadherin receptors, able to engage with receptors presented by neighbouring neuroepithelial cells, to integrate into embryoid bodies and developing organoids. The resulting artificial cells are able to sustain the formation of mature junctions with neighbouring cells and lead to the recruitment of tight junction maturation proteins such as ZO1. During early budding of neuroepithelial rosettes, artificial cells are found to be rapidly expelled from the developing organoids, further evidencing apical compressive forces. These forces are not opposed by sufficiently strong shear forces from neighbouring cells, or adhesive forces maintaining anchorage to the apical junction, to induce deformation of artificial cells.

Nanocatalytic therapy holds great promise in tumor treatment. However, its antitumor efficacy is substantially hindered by limitations of the tumor microenvironment (TME), including substrate the type and concentration of substrates, pH value, antioxidant stress defense mechanisms, and immunosuppressive milieu. This study presents a nanoplatform composed of manganese-in-situ-mineralized violet phosphorus nanosheets (VPNSs), abbreviated as MVPs. This platform enables both the disruption of redox homeostasis and activation of antitumor immunity through regulation by the TME and near-infrared II region (NIR-II) light stimulation. Within MVPs, VPNSs not only function as electron donors to sustain the concentration of active Mn in the TME and amplify the Mn-mediated self-enhanced chemodynamic therapy (CDT), but also serve as NIR-II photocatalysts. The photocatalytic properties synergistically elevate the level of reactive oxygen species (ROS) at the tumor site, thereby disrupting the redox homeostasis of tumor cells. Furthermore, the NIR-II photothermal characteristic of MVPs enhances the Mn-mediated activation of the stimulator of interferon genes (STING) pathway, endowing MVPs with antitumor immune activation capability. MVPs demonstrate excellent tumor therapeutic performance and biocompatibility in female tumor-bearing mice with a tumor inhibition rate of 85.24 %, achieving "catalysis-photothermal-immunity" synergistic antitumor activity.

Limited intratumoral drug accumulation and stemness-mediated immune evasion constitute fundamental barriers to effective immunotherapy in colorectal cancer (CRC). Tumor cell plasticity, fueled by metabolic reprogramming and cancer stemness, drives immunosuppressive microenvironment formation and therapeutic resistance. To overcome this, we engineered a purpurin-copper coordinated nanoplatform (TPGS/P-C@Ce6 NPs) that synergistically integrates cuproptosis induction, photodynamic therapy (PDT), and metabolic intervention. Critically, we demonstrate that surface-engineered d-α-tocopheryl polyethylene glycol succinate (TPGS) potently activates tumor cell macropinocytosis, significantly enhancing intracellular nanocarrier accumulation. Concurrently, purpurin reprograms glutamine metabolism via glutaminase inhibition, which enhances dendritic cell (DC) maturation and initiates T-cell priming. Furthermore, copper ion-driven cuproptosis synergizes with chlorin e6 (Ce6)-generated reactive oxygen species (ROS) to ablate cancer stemness, effecting robust conversion of immunologically cold tumors to T cell-inflamed hot phenotypes. Therefore, this tripartite strategy established durable immunological memory, with 100 % survival in rechallenged mice at 90 days post-treatment. This work establishes a novel metabolic-immunological co-regulation paradigm, providing a readily adaptable nanotherapeutic solution for CRC with high translational potential.

Surgical repair of pelvic organ prolapse (POP) is often augmented by polypropylene mesh to provide mechanical support to the vagina and improve anatomical outcomes as compared to native tissue repair. However, POP repair surgeries utilizing PPM have complications (most often pain or mesh exposure into the vagina) in over 10% of cases. Previous work has demonstrated that tensioning of meshes with certain geometries (diamond and hexagon pores), results in both planar (pore collapse) and nonplanar (wrinkles) deformations, significantly altering textile properties and impacting the host response. To further investigate the impact of mesh deformation on the host response, we implanted mesh in a validated non-human primate model via sacrocolpopexy with stable flat (square pores, N = 20) versus deformed geometries (mesh loaded on the diamond prior to implantation resulting in collapsed pores and wrinkles, N = 20). To investigate the impact of tension independent of deformation, we implanted on and off tension (10 N, N = 10 in each group). We hypothesized that more stable geometries trigger a healing response that achieves homeostasis while deformed mesh, by increasing the amount of material in contact with the host, triggers a maladaptive remodeling response with the formation of myofibroblasts. After twelve weeks, we found that mesh deformations and the absence of tension increase the amount of mesh per area on the vagina (mesh burden) and reproduced clinical complications (mesh exposure and vaginal thinning). Interestingly, MMT cells, or myofibroblasts co-expressing a macrophage marker (CD68), were seen to significantly increase in response to mesh burden, as well as respond hyper-locally to the mesh fiber interface. We observed decreased collagen density and more immature matrix deposited in conditions with higher MMT cell presence, showing more disorganization in deposited matrix with increased mesh burden, and the loss of tension. TGF-β1, in both active and latent forms, increased with increasing mesh burden, and highest expression was observed in conditions precipitating the highest percentage of MMT cells, a possible mechanism of transdifferentiation. This study showed the importance of PPM mesh properties on mesh burden following tensioning, impact on MMT transdifferentiation, and the downstream effect of these changes on the host response and healing outcomes.

Anastomosis is essential in cardiovascular surgery. However, traditional hand-sewn techniques are technically demanding, and existing sutureless methods often result in complications such as thrombosis and delayed healing due to poor mechanical compliance and insufficient endothelialization. Herein, we propose a cannula connection strategy that combines mechanical and biochemical support via a vascular-shaped polyetheretherketone (PEEK) connector. The PEEK substrate is coated with polydopamine (PDA) and chemically grafted with S-nitroso-N-acetylpenicillamine (SNAP) to enable sustained nitric oxide (NO) release. This approach significantly enhances anastomotic mechanical performance by improving tensile strength and burst pressure, thereby holding promise for reducing operation time and minimizing blood leakage. Compared to non-grafted SNAP coatings (PP-S), the chemically grafted version (PP@S) maintains elevated NO release for over 30 days, effectively modulating the local microenvironment, inhibiting platelet adhesion, and promoting the proliferation and spreading of human umbilical vein endothelial cells (HUVECs). In vivo studies show that the cannula device shortens surgical time by approximately 50 % and significantly decreases intraoperative bleeding. The mechanical structure offers resistance to pressure fluctuations, provides spatial reinforcement, and prevents anastomotic leakage. Concurrently, the biochemical modulation minimizes inflammatory responses and systemic toxicity, facilitating collagen fiber formation and further enhancing structural support. This positive feedback loop results in a 99.04 % anastomotic patency rate two months post-surgery. Overall, this integrated cannula strategy provides an alternative to traditional anastomosis techniques by combining mechanical and biochemical support to enhance anastomotic integrity and facilitate healing.

The translational potential of nanomedicines largely depends on compositional simplicity and scalable synthesis, with structurally intricate systems (e.g., hybrid composites) often struggling in manufacturing standardization. Single-element nanosystems bypass these limitations through inherent biosafety and bioactivity tunability. Herein, molybdenum nanodots (MoNDs), which synthesized via a facile and reproducible ultrasonic exfoliation method, were designed to address implant-associated osteolysis. These mono-component MoNDs displayed robust reactive oxygen species (ROS) scavenging and biocompatibility alongside recovering mitochondrial function to alleviate oxidative stress and curbing NF-κB-mediated M1 macrophage polarization. The MoNDs further regulated bone remodeling by suppressing osteoclastogenesis through NFATc1/CTSK downregulation and promoting osteogenic differentiation. In vivo evaluations using a titanium particle-induced osteolysis model revealed that the MoNDs effectively attenuated pathological bone loss, improved trabecular integrity, and rebalanced bone metabolic markers. Collectively, this work positions MoNDs as a clinically viable nanotherapeutic that harnesses elemental simplicity to resolve inflammation-driven osteolytic disorders, bridging material design with translational orthopedics.

Nanoparticle probes are advantageous over small molecular agents in medical imaging due to their prolonged circulation time, high payload capacity, and enhanced signal intensity. However, nanoparticle imaging probes are hindered by limited tissue penetration, often failing to provide sufficient contrast enhancement for imaging deep tissues. Herein, we developed a series of transcytosable iron oxide nanoparticles (TIONs) that penetrate deep tissue via cell transcytosis, enabling the T-weighted magnetic resonance imaging (MRI) of the internal tissues. To fabricate TIONs, we prepared iron oxide nanoparticles (IONs) modified with in situ growth of polylysine dendrimers of third generation, terminated with different β-carboxylic amides. The capacity of these IONs to induce cell internalization, exocytosis, and transcytosis was evaluated using a fluorescence-based high-throughput screening assay. Among them, G3-FiA and G3-DiA TIONs exhibited efficient transcytosis capability towards cancer cells. We further demonstrated the feasibility and efficacy of these TIONs for deep MRI of 4T1 subcutaneous tumors, GL261 subcutaneous and orthotopic glioma tumors. Additionally, we identified TIONs as effective agents for kidney-targeted deep tissue imaging, highlighting the applicability of the strategy for non-tumor tissue imaging. This study offers critical insights for designing nanoparticle-based delivery systems with enhanced tissue penetration, thereby advancing their potential for deep-tissue imaging applications.

Heterobimetallic nanozymes hold great promising in cancer catalytic therapy by leveraging dual-active sites that are electronically coupled. However, their therapeutic potential is limited by high inherent complexity and lack of clarity regarding their electron conformation. In this study, we developed a ligand coordination field engineering strategy to construct a cyano-bridged bimetallic nanozyme Cu[Fe(CN)] (SANE) with a well-defined electronic configuration for cancer catalytic-immunotherapy. Density functional theory (DFT) calculations revealed that cyano groups, acting as strong-field bridging ligands, could form an electron delocalization network. This network, driven by electronegativity gradient of the Cu (d) and Fe (d) bimetallic active centers, induces synergistic distortion of d-band energy levels, which in turn enhances electron transfer and significantly improves catalytic efficiency. Furthermore, the cyano-bridging, stabilizes the structure through a strong coordination field inhibiting metal aggregation, and allowing Cu to exhibit a single-atom distribution. This further strengthens SANE catalytic therapy ability. Biomimetic modification of SANE with immunogenic tumor exosomes (iEV) enhances biocompatibility, and provides efficient Peroxidase (POD)-like and Glutathione oxidase (GSHox)-like enzymatic activities within the tumor microenvironment achieving a catalytic-immune synergistic effect. This study provides a comprehensive framework to design heterobimetallic nanozyme with ideal catalytic structure from bimetallic active sites to bridged-ligand, opening a new avenue for precisely regulating of electronic configuration in catalytic-immunotherapeutic nanoplatform.

Piezocatalytic therapy, which utilizes ultrasonic activation of piezoelectric materials to generate reactive oxygen species (ROS), holds significant potential. However, its efficacy is constrained by the limited ROS generation capacity of piezoelectric materials. In this study, a gradient ion replacement strategy was employed to construct CuBaTiO-shell structured BaTiO (Cu-BTO) piezoelectric materials with flexoelectric properties. This process induces the BTO surface to transition from a crystalline state to an amorphous state and subsequently recrystallize. The phase transformation introduces flexoelectric properties in Cu-BTO surface, while the disparity in ionic radii between Cu and Ba enhances lattice asymmetry. Consequently, Cu-BTO exhibits significantly enhanced piezoelectric and piezocatalytic properties, with the d value reaching 129.91 pm/V, representing an increase of 345.93 %. Under ultrasonic stimulation, Cu-BTO can not only directly generate OH and HO through piezocatalysis, but also achieve self-amplified Fenton-like catalysis and GSH depletion by promoting charge transfer via the built-in electric field. The strong oxidative stress induces severe immunogenic cell death (ICD) of tumor cells, and triggers a series of antitumor immune responses such as dendritic cell (DC) maturation and T cell activation. Ultimately, an 83.7 % tumor inhibition rate is achieved, and lung metastasis of the tumor is effectively prevented. This work not only demonstrates a method to describes a method for inducing the flexoelectric effect in piezoelectric nanomaterials but also provides novel insights into the design and optimization of piezoelectric nanomaterials.

Physical stimuli have received significant attention, owing to their capacity to create more biomimetic niches. While dynamic mechanical loading has shown promise in promoting osteogenic and chondrogenic differentiation, magnetic fields have recently emerged as another potential stimulus. However, the combined effect of magnetomechanical - simultaneous magnetic and mechanical-stimulation on osteochondral tissue regeneration, remains largely unexplored. Moreover, a significant discrepancy exists across systems for magnetic stimulation in vitro, hindering cross-study comparison. Addressing these challenges, we developed a versatile, high-throughput device capable of delivering controlled magnetomechanical stimulation to 3D structures in vitro. When paired with magnetoactive, 3D printed scaffolds with low (mPLC5%) or high (mPLC20%) magnetic content, this system enabled the application of oscillating magnetic fields (0-300 mT) causing a cyclic mechanical displacement (0-2 μm). Magnetomechanical stimulation increased the expression of key osteogenic markers, including a 3-fold increase of alkaline phosphatase (ALP) and a 2-fold increase in osteocalcin concentration in mPLC5% scaffolds. Additionally, stimulated mPLC5% scaffolds showed a 2-fold increase in the relative expression of mechanotransduction markers compared to the mPLC20% condition. Moreover, a 3-fold increase in the expression of Collagen II and Aggrecan was observed in the stimulated mPLC20% scaffolds compared to their static counterparts, showing that this condition could be a potentially good candidate for chondrogenic commitment. Our findings suggest the presence of an optimal window for directing osteogenic or chondrogenic commitment, driven by the degree of cyclic deformation and the presence of the external oscillating magnetic field, in the absence of other differentiation stimuli.