BIOMATERIALS

M1-macrophage membrane-camouflaged nanoframeworks activate multiple immunity via calcium overload and photo-sonosensitization
Shen Y, Yu N, Zhao W, Niu S, Qiu P, Zeng H, Chen Z, Men W and Xie D
Immunotherapy is a powerful weapon for inhibiting tumor metastasis, while its efficacy is significantly compromised in immunosuppressive tumor microenvironment (TME). To reverse TME, this work has developed biomimetic nanoframeworks with calcium overload and photo-sonosensitization capacity to activate multiple immunities for metastasis inhibition. The biomimetic nanoframeworks were prepared by the assembly of Ca ions and Protoporphyrin IX (PpIX) into nanoframeworks (Ca-PpIX), and the encapsulation of M1 macrophage membrane (Ca-PpIX@M). They exhibit pH-dependent Ca ions release, O generation and photothermal conversion under external near-infrared light and ultrasound stimuli. The Ca-overload and elevated O cause oxidative stress within cells, leading to efficient mitochondrial dysfunction. Successively, the mitochondrial dysfunction induces a reduction in adenosine triphosphate (ATP) levels to inhibit the HSP90 expression, improving photothermal ablation's efficacy. The photo-sonosensitization has the ability to repolarize macrophages with the ratio of M1/M2 macrophage increasing from 0.25 to 2.45, which is better than monoactivation. Importantly, the Ca-PpIX@M also can induce the process of immunogenic cell death, resulting in the maturation of dendritic cells (30.2 %) and activation of cytotoxic (12.4 %) and helper T cells (19.7 %), thereby enhancing antitumor immunity in vivo. As a result, tumor growth and metastasis have been significantly inhibited. This work offers insights into developing biomimetic nanoframeworks to reverse TME for activating multiple immunity.
Autologous tumoral esterase-driven therapeutic polymers sequentially orchestrated antigen-induction, STING activation and anti-angiogenesis for systemic cancer immune therapy
Qiu N, Xu C, Zhang Z, Wang R, Wei X, Xie Y, Wang S, Lu D, Wang K, Xu S, Shen C, Su R, Cen B, Liu Y, Shen Y and Xu X
Effective cancer immune therapy requires the orchestration of antigen induction, presentation and T-cell activation, further enhanced by anti-angiogenesis treatment; therefore, multiple therapeutics are generally used for such combination therapy. Herein, we report esterase-hydrolysable cationic polymers, N-[3-((4-acetoxy benzyl) oxy)-3-oxopropyl]-N-methyl-quaternized PEI (ERP) and poly{N-[2-(acryloyl-oxy) ethyl]-N-[p-acetyloxyphenyl]-N,N-dimethylammonium chloride} (PQDMA), capable of simultaneously inducing tumor cell immunogenic cell death (ICD) to release antigens, activating the cGAS-STING pathways of tumor macrophages and dendritic cells, and releasing antiangiogenic agent p-hydroxybenzyl alcohol (HBA). Thus, intratumoral injection of ERP or PQDMA systemically boosted the anti-cancer immunities and inhibited tumor angiogenesis in mouse hepatocellular carcinoma and melanoma bilateral tumor models, leading to more effective tumor growth inhibition of both treated and abscopal untreated tumors than ICD alone induced by mitoxantrone and control cationic polymers. Further study using gene knockout mice and transcriptome sequencing analysis confirmed the involvement of cGAS-STING and type I IFN signaling pathways. This work demonstrates ERP and PQDMA as the first examples of inherent therapeutic polymers, accomplishing systemic tumor inhibition without combining other therapeutic agents.
Hybrid cell membrane coating orchestrates foreign-body reactions, anti-adhesion, and pro-regeneration in abdominal wall reconstruction
Yang L, Wang P, Zhang Y, Zhou J, Bi X, Qian Z, Hou S, Li L and Fan Y
Tension-free synthetic meshes are the clinical standard for hernia repair, but they often trigger immune response-mediated complications such as severe foreign-body reactions (FBR), visceral adhesions, and fibrotic healing, increasing the risk of recurrence. Herein, we developed a hybrid cell membrane coating for macroscale mesh fibers that acts as an immune orchestrator, capable of balancing immune responses with tissue regeneration. Cell membranes derived from red blood cells (RBCs) and platelets (PLTs) were covalently bonded to fiber surfaces using functionalized-liposomes and click chemistry. The fusion of clickable liposomes with cell membranes significantly improved coating efficiency, coverage uniformity, and in vivo stability. Histological and flow cytometric analyses of subcutaneous implantation in rats and mice demonstrated significant biofunctional heterogeneity among various cell membrane coatings in FBR. Specifically, the RBC-PLT-liposome hybrid cell membrane coating markedly mitigated FBR, facilitated host cell infiltration, and promoted M2-type macrophage polarization. Importantly, experimental results of abdominal wall defect repairs in rats indicate that the hybrid cell membrane coating effectively prevented visceral adhesions, promoted muscle regenerative healing, and enhanced the recruitment of Pax7/MyoD muscle satellite cells. Our findings suggest that the clickable hybrid cell membrane coating offers a promising approach to enhance clinical outcomes of hernia mesh in abdominal wall reconstruction.
Stromal fibrin shapes immune infiltration landscape of pancreatic ductal adenocarcinoma
Karim M, Hasan MM, Kim SH, Azam Z, Wahab R, Islam T, Alam F, Kim YJ, Bae DJ, Roy S, Grippo P, Bishehsari F, Choi JU and Al-Hilal TA
In pancreatic ductal adenocarcinoma (PDAC), in-situ coagulation creates a thrombotic, crosslinked fibrin (x-fibrin)-rich tumor stroma (FibTS), whose impact on immune cell behavior remains unclear. We aimed to elucidate how FibTS in PDAC regulates immune cell infiltration, polarization, and crosstalk that favors immunosuppressive microenvironment and tumor growth. We assessed the spatial distribution of immune cells by multiplex immunostaining of human PDAC tissues, along with novel bioengineering and mouse tumor models. We investigated how FibTS influences the infiltration of tumor-associated macrophage (TAM) and T-cell subtypes and identified two distinct variants of PDAC, fibrin-high (Fib) and fibrin-low (Fib). Our findings reveal that PDAC cells secrete fibrinogen and thrombin to form FibTS, which acts as a physical barrier and biochemical niche that restricts CD8 T-cell and TAM penetration into the tumor. The FibTS impeded immune cell penetration from the tumor stroma into the tumor parenchyma. Selective inhibition of FibTS formation by genetic and pharmacological tools altered the infiltration patterns of CD8 T-cells and TAMs, decelerating PDAC growth. This study demonstrates that the barrier function of FibTS is crucial for immune evasion, particularly against macrophage and T-cell activity, presenting a potential therapeutic strategy to reshape the immune landscape within PDAC and slow tumor progression.
Development of an electroconductive Heart-on-a-chip model to investigate cellular and molecular response of human cardiac tissue to gold nanomaterials
Esmaeili H, Zhang Y, Ravi K, Neff K, Zhu W, Migrino RQ, Park JG and Nikkhah M
To date, various strategies have been developed to construct biomimetic and functional in vitro cardiac tissue models utilizing human induced pluripotent stem cells (hiPSCs). Among these approaches, microfluidic-based Heart-on-a-chip (HOC) models are promising, as they enable the engineering of miniaturized, physiologically relevant in vitro cardiac tissues with precise control over cellular constituents and tissue architecture. Despite significant advancements, previously reported HOC models often lack the electroconductivity features of the native human myocardium. In this study, we developed a 3D electroconductive HOC (referred to as eHOC) model through the co-culture of isogenic hiPSC-derived cardiomyocytes (hiCMs) and cardiac fibroblasts (hiCFs), embedded within an electroconductive hydrogel scaffold in a microfluidic-based chip system. Functional and gene expression analyses demonstrated that, compared to non-conductive HOC, the eHOC model exhibited enhanced contractile functionality, improved calcium transients, and increased expression of structural and calcium handling genes. The eHOC model was further leveraged to investigate the underlying electroconduction-induced pathway(s) associated with cardiac tissue development through single-cell RNA sequencing (scRNA-seq). Notably, scRNA-seq analyses revealed a significant downregulation of a set of cardiac genes, associated with the fetal stage of heart development, as well as upregulation of sarcomere- and conduction-related genes within the eHOC model. Additionally, upregulation of the cardiac muscle contraction and motor protein pathways were observed in the eHOC model, consistent with enhanced contractile functionality of the engineered cardiac tissues. Comparison of scRNA-seq data from the 3D eHOC model with published datasets of adult human hearts demonstrated a similar expression pattern of fetal- and adult-like cardiac genes. Overall, this study provides a unique eHOC model with improved biomimcry and organotypic features, which could be potentially used for drug testing and discovery, as well as disease modeling applications.
A functional cardiac patch with "gas and ion" dual-effect intervention for reconstructing blood microcirculation in myocardial infarction repair
Zhao C, Liu J, Tian Y, Li Z, Zhao J, Xing X, Qiu X and Wang L
Postinfarction revascularization is critical for repairing the infarcted myocardium and for stopping disease progression. Considering the limitations of surgical intervention, engineered cardiac patches (ECPs) are more effective in establishing rich blood supply networks. For efficacy, ECPs should promote the formation of more mature blood vessels to improve microcirculatory dysfunction and mitigate hypoxia-induced apoptosis. Developing collateral circulation between infarcted myocardium and ECPs for restoring blood perfusion remains a challenge. Here, an ion-conductive composite ECPs (GMA@OSM) with powerful angiogenesis-promoting ability was constructed. Based on dual-effect intervention of oxygen and strontium, the developed ECPs can promote the formation of high-density circulating microvascular network at the infarcted myocardium. In addition, the GMA@OSM possesses effective reactive oxygen species-scavenging capacity and can facilitate electrophysiological repair of myocardium with ionic conductivity. In vitro and in vivo studies indicate that the multifunctional GMA@OSM ECPs form well-developed collateral circulation with infarcted myocardium to protect cardiomyocytes and improve cardiac function. Overall, this study highlights the potential of a multifunctional platform for developing collateral circulation, which can lead to an effective therapeutic strategy for repairing myocardial infarction.
Therapeutic potential of urinary extracellular vesicles in delivering functional proteins and modulating gene expression for genetic kidney disease
Huang Y, Osouli A, Li H, Dudaney M, Pham J, Mancino V, Khan T, Chaudhuri B, Pastor-Soler NM, Hallows KR and Chung EJ
Chronic kidney disease (CKD) is a widespread health concern, impacting approximately 600 million individuals worldwide and marked by a progressive decline in kidney function. A common form of CKD is autosomal dominant polycystic kidney disease (ADPKD), which is the most inherited genetic kidney disease and affects greater than 12.5 million individuals globally. Given that there are over 400 pathogenic PKD1/PKD2 mutations in patients with ADPKD, relying solely on small molecule drugs targeting a single signaling pathway has not been effective in treating ADPKD. Urinary extracellular vesicles (uEVs) are naturally released by cells from the kidneys and the urinary tract, and uEVs isolated from non-disease sources have been reported to carry functional polycystin-1 (PC1) and polycystin-2 (PC2), the respective products of PKD1 and PKD2 genes that are mutated in ADPKD. uEVs from non-disease sources, as a result, have the potential to provide a direct solution to the root of the disease by delivering functional proteins that are mutated in ADPKD. To test our hypothesis, we first isolated uEVs from healthy mice urine and conducted a comprehensive characterization of uEVs. Then, PC1 levels and EV markers CD63 and TSG101 of uEVs were confirmed via ELISA and Western blot. Following characterization of uEVs, the in vitro cellular uptake, inhibition of cyst growth, and gene rescue ability of uEVs were demonstrated in kidney cells. Next, upon administration of uEVs in vivo, uEVs showed bioavailability and accumulation in the kidneys. Lastly, uEV treatment in ADPKD mice (Pkd1;Pax8-rtTA;Tet-O-Cre) showed smaller kidney size, lower cyst index, and enhanced PC1 levels without affecting safety despite repeated treatment. In summary, we demonstrate the potential of uEVs as natural nanoparticles to deliver protein and gene therapies for the treatment of chronic and genetic kidney diseases such as ADPKD.
Manganese-based virus-mimicking nanomedicine with triple immunomodulatory functions inhibits breast cancer brain metastasis
Zhao Z, Zhou J, Li X, Zhang T, Tian Z, Sun T and Jiang C
Hindered by the challenges of blood-brain barrier (BBB) hindrance, tumor heterogeneity and immunosuppressive microenvironment, patients with breast cancer brain metastasis have yet to benefit from current clinical treatments, experiencing instead a decline in quality of life due to radiochemotherapy. While virus-mimicking nanosystems (VMN) mimicking viral infection processes show promise in treating peripheral tumors, the inability to modulate the immunosuppressive microenvironment limits the efficacy against brain metastasis. Accordingly, a VMN-based triple immunomodulatory strategy is initially proposed, aiming to activate innate and adaptive immune responses and reverse the immunosuppressive microenvironment. Here, manganese-based virus-mimicking nanomedicine (Vir-HD@HM) with intratumoral drug enrichment is engineered. Vir-HD@HM can induce the immune response through the activation of cGAS-STING by mimicking the in vivo infection process of herpesviruses. Meanwhile, DNAzyme mimicking the genome can rescue the epigenetic silencing of PTEN with the assistance of Mn, thus ameliorating the immunosuppressive metastatic microenvironment and achieving synergistic sensitizing therapeutic efficacy. In vivo experiments substantiate the efficacy of Vir-HD@HM in recruiting NK cells and CD8 T cells to metastatic foci, inhibiting Treg cells infiltration, and prolonging murine survival without adjunctive radiochemotherapy. This study demonstrates that Vir-HD@HM with triple immunomodulation offers an encouraging therapeutic option for patients with brain metastasis.
Magnesium hexacyanoferrate mitigates sepsis-associated encephalopathy through inhibiting microglial activation and neuronal cuproptosis
Zhang Y, Xin J, Zhao D, Chen G, Ji P, Liu P, Wei H, Wang H, Xia Y, Wang Y, Wang Z, Ren X, Huo M, Yu H and Yang J
Sepsis-associated encephalopathy (SAE) is a severe neurological complication stemming from sepsis, characterized by cognitive impairment. The underlying mechanisms involve oxidative stress, neuroinflammation, and disruptions in copper/iron homeostasis. This study introduces magnesium hexacyanoferrate (MgHCF) as a novel compound and explores its therapeutic potential in SAE. Our investigation reveals that MgHCF features intriguing properties in effectively scavenging reactive oxygen species (ROS), and chelating excess copper and iron. Treatment with MgHCF significantly attenuates microglia activation, and protects neuronal cells from oxidative damage and cytotoxicity induced by activated microglia in vitro and in vivo. Furthermore, the cognitive impairment in SAE mice is effectively alleviated by MgHCF treatment, mechanically through a reduction in the copper/iron-responsive histone methylation, and neuronal cuproptosis. These findings suggest MgHCF as a promising therapeutic agent for SAE, targeting the copper/iron signaling pathway to alleviate neuroinflammation, and neuronal cuproptosis.
Selective vascular disrupting therapy by lipid nanoparticle-mediated Fas ligand silencing and stimulation of STING
Endo R, Ueda T, Nagaoki T, Sato Y, Maishi N, Hida K, Harashima H and Nakamura T
Although recent therapeutic developments have greatly improved the outcomes of patients with cancer, it remains on ongoing problem, particularly in relation to acquired drug resistance. Vascular disrupting agents (VDAs) directly damage tumor blood vessels, thus promoting drug efficacy and reducing the development of drug resistance; however, their low molecular weight and resulting lack of selectivity for tumor endothelial cells (TECs) lead to side effects that can hinder their practical use. Here, we report a novel tumor vascular disrupting therapy using nucleic acid-loaded lipid nanoparticles (LNPs). We prepared two LNPs: a small interfering RNA (siRNA) against Fas ligand (FasL)-loaded cyclic RGD modified LNP (cRGD-LNP) to knock down FasL in TECs and a stimulator of interferon genes (STING) agonist-loaded LNP to induce systemic type I interferon (IFN) production. The combination therapy disrupted the tumor vasculature and induced broad tumor cell apoptosis within 48 h, leading to rapid and strong therapeutic effects in various tumor models. T cells were not involved in these antitumor effects. Furthermore, the combination therapy demonstrated a significantly superior therapeutic efficacy compared with conventional anti-angiogenic agents and VDAs. RNA sequencing analysis suggested that reduced collagen levels may have been responsible for TEC apoptosis. These findings demonstrated a potential therapeutic method for targeting the tumor vasculature, which may contribute to the development of a new class of anti-cancer drugs.
STING-activating layered double hydroxide nano-adjuvants for enhanced cancer immunotherapy
Jia L, Qin Y, Li X, Liu H, He Z and Wang Y
Cancer vaccines represent a promising therapeutic strategy in oncology, yet their effectiveness is often hampered by suboptimal antigen targeting, insufficient induction of cellular immunity, and the immunosuppressive tumor microenvironment. Advanced delivery systems and potent adjuvants are needed to address these challenges, though a restricted range of adjuvants for human vaccines that are approved, and even fewer are capable of stimulating robust cellular immune response. In this work, we engineered a unique self-adjuvanted platform (MLDHs) by integrating STING agonists manganese into a layered double hydroxide nano-scaffold, encapsulating the model antigen ovalbumin (OVA). The MLDHs platform encompasses Mn-doped MgAl-LDH (MLMA) and Mn-doped MgFe-LDH (MLMF). Upon subcutaneous injection, OVA/MLDHs specifically accumulated within lymph nodes (LNs), where they were internalized by resident antigen-presenting cells. The endosomal degradation of MLDHs facilitated the cytoplasmic release of antigen and Mn, promoting cross-presentation and triggering the STING pathway, which in turn induced a potent cellular immune response against tumors. Notably, OVA/MLMF induced stronger M1 macrophage polarization and a more potent T-cell response within tumor-infiltrating lymphocytes compared to OVA/MLMA, leading to significant tumor regression in B16F10-OVA bearing mice with minimal adverse effects. Additionally, combining MLMF with the vascular disrupting agent Vadimezan disrupted the tumor's central region, typically resistant to immune cell infiltration, further extending survival in tumor-bearing mice. This innovative strategy may show great potential for improving cancer immunotherapy and offers hope for more effective treatments in the future.
A remotely controlled nanotherapeutic with immunomodulatory property for MRSA-induced bone infection
Zhao Z, Zhang Y, Li J, Huang S, Xing G, Zhang K, Ma X, Zhang X and Zhang Y
Osteomyelitis is a deep bone tissue infection caused by pathogenic microorganisms, with the primary pathogen being methicillin-resistant Staphylococcus aureus (MRSA). Due to the tendency of the infection site to form biofilms that shield drugs and immune cells to kill bacteria, combined with the severe local inflammatory response causing bone tissue destruction, the treatment of osteomyelitis poses a significant challenge. Herein, we developed a remotely controlled nanotherapeutic (TLBA) with immunomodulatory to treat MRSA-induced osteomyelitis. TLBA, combined with baicalin and gold nanorods, is positively charged to actively target and penetrate biofilms. Near-infrared light (808 nm) triggers spatiotemporal, controllable drug release, while bacteria are eliminated through synergistic interaction of non-antibiotic drugs and photothermal therapy, enhancing bactericidal efficiency and minimizing drug resistance. TLBA eliminated nearly 100 % of planktonic bacteria and dispersed 90 % of biofilms under NIR light stimulation. In MRSA-induced osteomyelitis rat models, laser irradiation raised the infection site temperature to 50 °C, effectively eradicating bacteria, promoting M2 macrophage transformation, inhibiting bone inflammation, curbing bone destruction, and fostering bone tissue repair. In summary, TLBA proposes a more comprehensive treatment strategy for the two characteristic pathological changes of bacterial infection and bone tissue damage in osteomyelitis.
MRI-responsive nanoprobes for visualizing hydrogen peroxide in diabetic liver injury
Fan X, Sun Y, Fu J, Cao H, Liao S, Zhang C, Huan S and Song G
Diabetic liver injury has emerged as a significant complication associated with diabetes, warranting increased attention. The generation of hydrogen peroxide (HO) due to oxidative stress plays a critical role in the onset and progression of this condition. Despite this, there is a scarcity of probes capable of non-invasively, accurately, and reliably visualizing HO levels in deep-seated liver in diabetes-induced liver injury. In this study, we introduce a novel HO-responsive magnetic probe (HO-RMP), designed for the sensitive imaging of HO in the liver injury caused by diabetes. HO-RMP is synthesized through the co-precipitation of a HO-responsive amphiphilic polymer, manganese(III) porphyrin (Mn-porphyrin), and iron oxide nanoparticles. When exposed to HO, the released iron oxide nanoparticles aggregate, resulting in an increased T-weighted MR signal intensity. HO-RMP not only demonstrates a wide dynamic response range (initial r = 9.87 mMs, Δr = 7.69 mMs), but also exhibits superior selectivity for HO compared to other reactive oxygen species. Importantly, HO-RMP exhibits high sensitivity, with a detection limit for hydrogen peroxide as low as 0.56 μM. Moreover, HO-RMP has been effectively applied for real-time imaging of HO levels in the livers of diabetic model mice with varying degrees of severity, highlighting its potential for visual diagnosis and monitoring the progression of diabetic liver injury.
In situ forming AIEgen-alginate hydrogel for remodeling tumor microenvironment to boost FLASH immunoradiotherapy
Lyu M, Zhang T, Bao Z, Li P, Chen M, Quan H, Wang C, Xia L, Li Y and Tang B
FLASH radiotherapy, which involves the delivery of an ultra-high radiation dose rate exceeding 40 Gy/s, has emerged as a promising tumor ablation strategy. While this approach generally spares normal tissues, the incomplete killing of tumors may sometimes lead to recurrence due to the immunosuppressive tumor microenvironment (TME). Herein, an aggregation-induced-emission luminogen (AIEgen)-alginate hydrogel was used to sensitize colon cancer via photodynamic therapy (PDT). Flower-like calcium carbonate nanoparticles, doped with an AIEgen termed CQu, were designed and applied as a cocktail with sodium alginate. When exposed to the acidic TME, Ca is released from this structure, resulting in sodium alginate termed FA forming a hydrogel in situ within the TME. This hydrogel also captures high concentrations of CQu in the local TME. Under laser irradiation, the CQu can generate sustained reactive oxygen species (ROS) production, thereby facilitating Ca influx and causing mitochondrial damage. Through a single injection of established FA hydrogel, followed by PDT and FLASH radiotherapy, immunogenic tumor cell death was induced which promoted antitumor immunity, thereby protecting against tumor recurrence while realizing abscopal effect. The results highlight the potential to improve the sensitivity of tumor cells to FLASH radiotherapy through sustained ROS production and Ca overload, thereby yielding optimal immunotherapy outcomes.
Immunomodulatory bioadhesive technologies
Lan X, Johnston E, Ning T, Chen G, Haglund L and Li J
Bioadhesives have found significant use in medicine and engineering, particularly for wound care, tissue engineering, and surgical applications. Compared to traditional wound closure methods such as sutures and staples, bioadhesives offer advantages, including reduced tissue damage, enhanced healing, and ease of implementation. Recent progress highlights the synergy of bioadhesives and immunoengineering strategies, leading to immunomodulatory bioadhesives capable of modulating immune responses at local sites where bioadhesives are applied. They foster favorable therapeutic outcomes such as reduced inflammation in wounds and implants or enhanced local immune responses to improve cancer therapy efficacy. The dual functionalities of bioadhesion and immunomodulation benefit wound management, tissue regeneration, implantable medical devices, and post-surgical cancer management. This review delves into the interplay between bioadhesion and immunomodulation, highlighting the mechanobiological coupling involved. Key areas of focus include the modulation of immune responses through chemical and physical strategies, as well as the application of these bioadhesives in wound healing and cancer treatment. Discussed are remaining challenges such as achieving long-term stability and effectiveness, necessitating further research to fully harness the clinical potential of immunomodulatory bioadhesives.
Design of NanoBiT-Nanobody-based FGL1 biosensors for early assisted diagnosis of esophageal cancer
Li L, Lan Z, Qiao H, Meng X, Shi Z, Zhang W, Wang Y, Sun Z, Cui Q, Wang L, Zhou S, Hu F, Zhang D, Dai Y, Chen H and Geng Y
Esophageal cancer (EC) is one of the most common causes of cancer-related mortality due in part to challenges in early diagnosis. Biomarker identification is crucial for improved early screening and treatment strategies for patients. Firstly, we employed serum proteomics techniques to screen for potential biomarkers in 15 early-stage EC patients and 5 healthy individuals. Among the differentially expressed proteins, FGL1 emerged as a promising candidate (AUC = 0.974) for early detection of EC. Subsequently, we developed NanoBiT-conjugated dual nanobodies (NBNB) sensors for robust and quantitative signal detection in fetal bovine serum (FBS) in 30 min or less, with a limit of detection (LoD) of 11.38 pM. In a case-control study recruiting 96 EC patients and 99 control samples, testing serum samples with the developed NBNB sensors revealed significantly elevated serum level of FGL1 in all-stage EC patients (AUC = 0.7880) and early-stage EC patients (AUC = 0.8286). Additionally, the combined diagnostic performance of FGL1 and CEA in EC samples is notably enhanced (AUC = 0.8847). These findings propose FGL1 as a novel and promising target for the early-stage EC diagnosis and treatment selection. Furthermore, we applied the assay to patients across six types of cancer, suggesting FGL1 as a potential pan-cancer marker. This study introduces a rapid, easy-to-use, cost-effective, reliable, universal, and high-throughput alternative to meet the growing demand for cancer biomarker testing in both academic and clinical settings.
Development of an innovative extracellular vesicle mimetic delivery platform for efficient miRNA delivery to tumours
Chen R, Bhavsar C, Lourie R, Li S and Wu SY
Extracellular vesicles (EVs) display high degree of tissue tropism and therefore represent promising carriers for tissue-specific delivery of genes or drugs for the treatment of human diseases. However, current approaches for the loading of therapeutics into EVs have low entrapment efficiency and also do not adequately deplete endogenous EV content; thus, more effective approaches are needed. Here, we report an innovative EXtraCElluar vesicle surface Ligand-NanoParticles (EXCEL NPs), generated by transferring moieties of EVs onto the surface of synthetic nanoparticles. EXCEL NPs facilitate the efficient entrapment of therapeutics (89 % efficiency) and are completely devoid of pre-existing unwanted EV internal content. Importantly, we show that EXCEL NPs formulated using EVs derived from endothelial cells, astrocytes and macrophages retain the delivery characteristics of the original EVs. Using miRNA-146a as a model anti-cancer therapeutic, we further demonstrated successful delivery of miRNA-146a to IG10 orthotopic ovarian tumours in immune competent mice using EXCEL NPs formulated with macrophage-derived EVs. Our findings establish a new clinically translatable approach to leverage characteristics of endogenous EVs for therapeutic delivery. The versatility of the platform enables future application to different target cell types and therapeutic modalities.
Force-electric biomaterials and devices for regenerative medicine
Yao S, Cui X, Zhang C, Cui W and Li Z
There is a growing recognition that force-electric conversion biomaterials and devices can convert mechanical energy into electrical energy without an external power source, thus potentially revolutionizing the use of electrical stimulation in the biomedical field. Based on this, this review explores the application of force-electric biomaterials and devices in the field of regenerative medicine. The article focuses on piezoelectric biomaterials, piezoelectric devices and triboelectric devices, detailing their categorization, mechanisms of electrical generation and methods of improving electrical output performance. Subsequently, different sources of driving force for electroactive biomaterials and devices are explored. Finally, the biological applications of force-electric biomaterials and devices in regenerative medicine are presented, including tissue regeneration, functional modulation of organisms, and electrical stimulation therapy. The aim of this review is to emphasize the role of electrical stimulation generated by force-electric conversion biomaterials and devices on the regulation of bioactive molecules, ion channels and information transfer in living systems, and thus affects the metabolic processes of organisms. In the future, physiological modulation of electrical stimulation based on force-electric conversion is expected to bring important scientific advances in the field of regenerative medicine.
Investigation of the biodegradation kinetics and associated mechanical properties of 3D-printed polycaprolactone during long-term preclinical testing
Ramaraju H, Verga AS, Steedley BJ, Kowblansky AP, Green GE and Hollister SJ
Polycaprolactone (PCL) is a bioresorbable polymer increasingly utilized for customized tissue reconstruction as it is readily 3D printed. A critical design requirement for PCL devices is determining the in vivo bioresorption rate and the resulting change in device mechanics suited for target tissue repair applications. The primary challenge with meeting this requirement involves accurate prediction of degradation in the target tissues. PCL undergoes bulk hydrolytic degradation following first order kinetics until an 80-90 % drop in the starting number average molecular weight (Mn) after 2-3 years in vivo. However, initial polymer architecture, composite incorporation, manufacturing modality, device architecture, and target tissue can impact degradation. In vitro models do not fully capture device degradation, and the limited long-term (2-3 year) models primarily utilize subcutaneous implants. In this study, we investigate the degradation rate of 3D-printed airway support devices (ASDs) comprised of PCL and 4 % hydroxyapatite (HA) when implanted on Yucatan porcine tracheas for two years. After one year of degradation, we report a mass loss of less than 1 % and Mn reduction of 25 %. After two years, mass and Mn decreased by 10 % and 50 % respectively. These changes are accompanied by an increase in elastic modulus from 146.7 ± 5.2 MPa for freshly printed ASDs to 291.7 ± 16.0 MPa after one year and 362.5 ± 102.4 MPa after two years. Additionally, there was a decrease in yield strain, and increase in yield stress from implantation to 1-year (p < 0.001). Plastic strain completely diminished by two years, resulting in brittle failure at a yield stress of 12.5 MPa. The significantly lower rate of hydrolysis coupled with hydrolytic embrittlement indicates alternate degradation kinetics compared to subcutaneous models. Fitting a new model for degradation and predicting elastic and damage properties of this new degradation paradigm provide significant advancements for 3D-printed device design in clinical repair applications.
3D bioprinted microfluidic based osteosarcoma-on-a chip model as a physiomimetic pre-clinical drug testing platform for anti-cancer drugs
Jaiswal C, Dey S, Prasad J, Gupta R, Agarwala M and Mandal BB
Standard chemotherapeutic regimen for osteosarcoma (OS) treatment often leads to poor therapeutic outcome, primarily due to lack of an adequate representative model reflecting native OS structural and cellular complexity, posing a translational gap. Three-dimensional bioprinting (3D-BP) represents an efficient and advanced technique for precise recapitulation of the structural and cellular complexity of OS tumor microenvironment (TME). In the present study, we employed a dual extrusion-based 3D-BP method to develop an improved in vitro OS model consisting of both tumor and stromal components. Additionally, a human physiomimetic microfluidic bioreactor is introduced to mimic the dynamic TME and provide physiologically relevant mechanical stimulation to the cells. The model named TC-OS model, demonstrated close resemblance to native OS-TME, validated by in vitro studies. Continuous media flow provided mechanical stimulation in the form of shear stress, positively influencing the growth and aggressiveness of OS. Further, drug screening with the model anticancer drugs (doxorubicin, cis-platin, sorafenib) demonstrated enhanced sensitivity in TC-OS model as compared to TC-OS model, emphasizing enhanced mass transfer, availability and distribution of anticancer drug due to continuous media flow. Overall, TC-OS model holds significant potential as a platform in future for high throughput pre-clinical screening of anticancer drugs.
Nanomaterial technologies for precision diagnosis and treatment of brain hemorrhage
Zhang P, Ran Y, Han L, Li Y, Tian W, Sun X, Jiao M, Jing L and Luo X
Brain hemorrhage events present complex clinical challenges due to their rapid progression and the intricate interplay of oxidative stress, inflammation, and neuronal damage. Traditional diagnostic and therapeutic approaches often struggle to meet the demands for timely and effective intervention. This review explores the cutting-edge role of nanomaterials in transforming cerebral hemorrhage management, focusing on both diagnostic and therapeutic advancements. Nanomaterial-enabled imaging techniques, such as optical imaging, magnetic resonance imaging, and magnetic particle imaging, significantly enhance the accuracy of hemorrhage detection by providing real-time, high-resolution assessments of blood-brain barrier (BBB) integrity, cerebral perfusion, and hemorrhage progression, which is critical for guiding intervention strategies. On the therapeutic front, nanomaterial-based systems enable the precise delivery of drugs and bioactive molecules, fostering neural repair and functional recovery while minimizing systemic side effects. Furthermore, multifunctional nanomaterials not only address the primary injury but also offer precise control over secondary injuries, such as edema and oxidative stress. Their ability to enhance neuroprotection, prevent re-bleeding, and stimulate brain tissue regeneration provides a holistic approach and marks a significant advancement in brain hemorrhage therapy. As the field continues to advance, nanotechnology is set to fundamentally reshape the clinical management and long-term outcomes of brain hemorrhages, presenting a paradigm shift towards personalized and highly effective neurological care.