Biomaterials[JOURNAL]
Sun
200 papers
A natural synergistic repair hydrogel with disulfide COF core breaks the vicious cycle of diabetic wounds in rabbits.
Hu D, Zhuang J, Xue J … +2 more , Wang K, Zhang G
Biomaterials · 2026 Jun · PMID 42251781 · Publisher ↗
Diabetic chronic wounds present a formidable clinical challenge driven by a self-perpetuating cycle of hyperglycaemia-induced oxidative stress, persistent inflammation, and recurrent infection. Conventional wound dressin...
Diabetic chronic wounds present a formidable clinical challenge driven by a self-perpetuating cycle of hyperglycaemia-induced oxidative stress, persistent inflammation, and recurrent infection. Conventional wound dressings often fail to address these complexities, primarily due to their lack of inherent multifunctionality and stimuli-responsive capabilities. To overcome these limitations, we develop a smart, redox-responsive hydrogel that integrates a disulfide-bridged covalent organic framework (S-COF) loaded with various natural bioactives, including curcumin, gallic acid, vanillin, and carboxymethyl chitosan. This multifunctional hydrogel facilitates sustained and on-demand therapeutic release in direct response to the wound microenvironment, while exerting synergistic antioxidant, antibacterial, and anti-inflammatory effects. In vitro assays using clinical diabetic blood samples demonstrated efficient reactive oxygen species scavenging, pathogen inhibition, and increased superoxide dismutase activity. In a diabetic rabbit wound model, this COF-based hydrogel significantly accelerated healing by reducing the inflammatory phase and promoting angiogenesis and collagen deposition, resulting in approximately 90% wound closure, a marked improvement over the 50% closure in untreated controls. Additionally, the hydrogel exhibited excellent biocompatibility, evidenced by a hemolysis rate of <1%. This natural-product-derived, redox-responsive platform simultaneously targets multiple pathological pathways, offering a robust and versatile strategy for advanced diabetic wound therapy.
Hydrophilicity engineering of amphiphilic macrocyclic MRI contrast agents for enhanced hepatic targeting efficiency.
Jiang Y, Cai Z, Gu H … +13 more , Fu S, Cao Y, Li N, Liu L, Fu X, Xia C, Su F, Sun H, Luo K, Lui S, Song B, Gong Q, Ai H
Biomaterials · 2026 Jun · PMID 42251780 · Publisher ↗
Effective hepatic enhancement and high kinetic inertness are pivotal driving forces for developing gadolinium-based hepatobiliary MRI contrast agents (CAs). Although lipophilic modifications have dominated efforts to pro...
Effective hepatic enhancement and high kinetic inertness are pivotal driving forces for developing gadolinium-based hepatobiliary MRI contrast agents (CAs). Although lipophilic modifications have dominated efforts to promote hepatic uptake, the vital role of hydrophilicity has been overlooked. Herein, we investigated the structure-activity relationship by fine-tuning of an amphiphilic macrocyclic complex through hydrophilicity engineering. The water-soluble Gd-HE(BnOPh)-DO3A exhibited exceptional kinetic inertness with a dissociation half-life of 8.3 h at pH 1.2, nearly 5-fold longer than the 1.7 h observed for the non-hydroxyl Gd-BnOBn-DO3A. More importantly, Gd-HE(BnOPh)-DO3A achieved rapid and pronounced hepatic enhancement, with a 3.1-fold increase in signal intensity observed as early as 2 min post-injection, while the amphiphilic Gd-BnOBn-DO3A displayed delayed hepatic enhancement, peaking at 30 min. These markedly different pharmacokinetic profiles might arise from altered molecular assembly behavior. Hydroxyl incorporation in Gd-HE(BnOPh)-DO3A disrupted amphiphilic equilibrium and prevented nanoparticle self-assembly, enabling rapid hepatic enhancement in the form of small molecules. Conversely, Gd-BnOBn-DO3A dynamically formed nanoparticles with hydrodynamic size over 200 nm, leading to slower hepatic uptake. In summary, this work established strategic hydrophilicity engineering as an effective, previously underappreciated approach to optimizing hepatic targeting of CAs, offering unique insights into MRI agent design.
Piezocatalytic nanotransducers rewire tumor immunometabolism via in situ peroxynitrite generation.
Zhang J, Yan J, Ye K … +9 more , Fu Y, Dong Z, Zhang X, He Y, Liu Y, Yan X, Xue W, Tu W, Gao D
Biomaterials · 2026 Jun · PMID 42247928 · Publisher ↗
The dense extracellular matrix (ECM) and stromal cells in breast cancer constitute a formidable physical and immunosuppressive barrier that facilitates immune evasion and tumor progression. Within this desmoplastic micro...
The dense extracellular matrix (ECM) and stromal cells in breast cancer constitute a formidable physical and immunosuppressive barrier that facilitates immune evasion and tumor progression. Within this desmoplastic microenvironment, cancer-associated fibroblasts (CAFs) overexpress indoleamine 2,3-dioxygenase-1 (IDO-1), an enzyme that activates the tryptophan-kynurenine metabolic pathway to induce T cell exhaustion and immune tolerance. Consequently, modulating tryptophan metabolism in CAFs represents a promising strategy to potentiate antitumor immunotherapy. Herein, we develop a CAF-targeted nanomedicine system based on dasatinib-loaded NbGeTe (NGT) nanosheets for ultrasound-mediated immunometabolic modulation. Under low-intensity ultrasound, NGT exhibits efficient piezocatalytic charge separation, efficiently separating electron-hole pairs to trigger the generation of superoxide anions (·O). These reactive species rapidly react with intracellular nitric oxide to form peroxynitrite (ONOO), which induces site-specific tyrosine nitration of IDO-1. This process irreversibly inactivates IDO-1, thereby disrupting the tryptophan-kynurenine immunosuppressive axis. Simultaneously, the controlled release of dasatinib inhibits CAF-mediated fibrosis, dismantling the stromal barrier, reducing tumor stiffness and facilitating the infiltration of cytotoxic T lymphocytes. This study establishes a precise piezocatalysis-driven strategy for reprogramming the tumor microenvironment in desmoplastic malignancies, providing a promising avenue for the development of two-dimensional nanomaterials in cancer immunotherapy.
Towards the clinical translation of a novel autophagy inhibitor: Bisaminoquinoline derivative nanoparticles.
Mahri S, Tang M, Zong Q … +3 more , Kim EJ, Lin TY, Li Y
Biomaterials · 2026 Jun · PMID 42247927 · Publisher ↗
Targeting autophagy is a promising strategy to sensitize tumors and overcome drug resistance. BAQ13, a novel autophagy inhibitor that self-assembles into nanoparticles, has demonstrated potent antitumor activity in precl...
Targeting autophagy is a promising strategy to sensitize tumors and overcome drug resistance. BAQ13, a novel autophagy inhibitor that self-assembles into nanoparticles, has demonstrated potent antitumor activity in preclinical models; however, effective clinical translation requires establishing safety and tolerability using a stable and clinical-grade formulation. Here, we report the development and manufacturing of BAQ13-loaded lipid nanoparticles (BAQ13-LNP) using a scalable fluidic approach. BAQ13 was efficiently incorporated with helper lipids (SPC, DSPE-PEG2K, cholesterol), producing uniform nanoparticles (<75 nm, PDI ∼0.2) with complete encapsulation. Long-term shelf stability was achieved through lyophilization with 9% w/v sucrose, preserving the formulation for at least two years at 2-8 °C, while multi-gram production under current Good Manufacturing Practice (cGMP) ensured compliance with USP standards for injectable formulations, establishing readiness for clinical use. BAQ13 retained activity in a broad panel of human cancer cell lines, including those resistant to standard therapies. In pancreatic mouse tumor model, BAQ13-LNP efficiently accumulated in and penetrated deeply into tumor tissue, effectively inhibited tumor growth, and prolonged survival. Together with its favorable safety profile, these data supported the initiation of a Phase 1 clinical trial evaluating BAQ13-LNP (TR-002) as an autophagy inhibitor in patients with solid tumors (NCT07189195).
Nasal microenvironment self-responsive herbal hydrogel alleviates Parkinsonian pathology via the inhibition of α-synuclein liquid-liquid phase separation.
Cheng G, Yin C, Zhu X … +10 more , Wang Y, Wei Y, Tan Y, Zheng J, Zheng C, Xiao L, Sui S, Chen X, Zhang Y, Chen T
Biomaterials · 2026 Jun · PMID 42247926 · Publisher ↗
The liquid-liquid phase separation (LLPS) of α-synuclein (α-syn) is recognized as a critical driver of Parkinson's disease (PD) progression. Therefore, inhibiting α-syn LLPS may confer anti-Parkinsonian therapy. Although...
The liquid-liquid phase separation (LLPS) of α-synuclein (α-syn) is recognized as a critical driver of Parkinson's disease (PD) progression. Therefore, inhibiting α-syn LLPS may confer anti-Parkinsonian therapy. Although some small-molecule inhibitors effectively suppress α-syn LLPS, their limited delivery across the blood-brain barrier (BBB) hinders their application. In this study, the natural product baicalein (BA) was found to inhibit α-syn LLPS, and a BA-loaded nasal hydrogel was developed for PD therapy. To avoid the rapid clearance of BA within the nasal cavity, BA was formulated onto the skeleton of carboxymethyl chitosan and 4-formylphenylboronic acid through dynamic intermolecular self-assembly to produce a mucoadhesive hydrogel (CAB2). CAB2 exhibited self-responsive drug release in the weakly acidic and reactive oxygen species-rich microenvironment of the nasal cavity, allowing BA to bypass the BBB and efficiently accumulate in the brain. CAB2 retained the ability of BA to inhibit α-syn LLPS and possessed favorable neuroprotective and anti-neuroinflammatory effects. The therapeutic efficacy of CAB2 extended beyond α-syn LLPS suppression, such that CAB2 also restored autophagic flux, ameliorated oxidative damage, and attenuated neuroinflammatory responses, thus comprehensively remodeling the PD-associated pathological microenvironment. Therefore, this herbal hydrogel capable of self-responsive release in the nasal microenvironment offers a novel therapeutic option for PD.
Bifunctional ferritin nanoparticle blocks PD-1/PD-L1 pathway and alleviates oxidative stress for multi-target therapy of multiple sclerosis.
Yang S, Sun K, He R … +5 more , Wang N, Li M, Yang W, Jia Y, Duan R
Biomaterials · 2026 May · PMID 42242097 · Publisher ↗
To address the limited immunotargeting specificity of PD-L1 antibodies and the exacerbated oxidative stress microenvironment in multiple sclerosis (MS), a bifunctional nanoplatform, Ru@Fn-PD-L1(IgV), was developed using...
To address the limited immunotargeting specificity of PD-L1 antibodies and the exacerbated oxidative stress microenvironment in multiple sclerosis (MS), a bifunctional nanoplatform, Ru@Fn-PD-L1(IgV), was developed using an engineered ferritin nanocage. This system was constructed via site-specific conjugation of the PD-L1 extracellular domain(IgV) to ferritin using SpyTag-SpyCatcher bioconjugation, combined with the in-situ encapsulation of ruthenium-based nanozymes exhibiting superoxide dismutase/catalase (SOD/CAT) cascade activity within the nanocage. Ru@Fn-PD-L1 (IgV) efficiently traverses the blood-brain barrier (BBB) through transferrin receptor (TfR1)-mediated transcytosis, enabling targeted delivery to the central nervous system (CNS). Mechanistic studies demonstrated that Ru@Fn-PD-L1(IgV) selectively inhibits the programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) signaling axis in activated T cells, thereby promoting apoptosis and suppressing pro-inflammatory cytokine secretion. Concurrently, the nanozymes effectively scavenge reactive oxygen species (ROS), including superoxide anions (O·), and hydrogen peroxide (HO), and induce polarization of microglia toward the M2 anti-inflammatory phenotype, substantially alleviating oxidative stress and neuroinflammatory injury. In vivo studies using a mouse model of MS demonstrated significant neuroprotection and enhanced cognitive performance, supporting the potential of Ru@Fn-PD-L1(IgV) as a novel immunotherapeutic strategy for treating MS.
Nitrogen-doped nano-mosaic with platelet membrane reversely targets neutrophils to break the ROS-NETs circuit in diabetic periodontitis.
Wang H, Tuerhong K, Zhang Q … +12 more , Luo X, Zhang J, Chen Y, Jiang X, Huang Q, Su X, Dang H, Wang M, Liu Y, Yang S, Li Y, Song J
Biomaterials · 2026 May · PMID 42235461 · Publisher ↗
Efficient bio-targeting and potent ROS scavenging are required to alleviate neutrophil extracellular trap (NET)-mediated tissue destruction in diabetic periodontitis (DP); however, current pharmaceutical therapies are li...
Efficient bio-targeting and potent ROS scavenging are required to alleviate neutrophil extracellular trap (NET)-mediated tissue destruction in diabetic periodontitis (DP); however, current pharmaceutical therapies are limited by insufficient catalytic activity and poor tissue specificity. Herein, by integrating guanidyl-rich metformin (Met) into the Fe-Curcumin (Cur) framework, we reconstruct the enzymatic center from a naive trivalent Fe-O motif into a saturated octahedral Fe-N/O configuration. This high-coordination environment facilitates the stabilization of high-valent iron intermediates, thereby significantly boosting catalytic performance. Inspired by the natural recruitment of neutrophils by activated platelets, encapsulation with a platelet membrane (PM) camouflage endows this nano-mosaic with a reverse-targeting capability. By leveraging the specific P-selectin/PSGL-1 interaction to anchor onto inflammation-homing neutrophils, the nanozymes effectively 'hitchhike' to the periodontal lesion. Synchrotron-based spectroscopy, theoretical simulations, and in vitro biochemical assays confirm that this transformation elicits a 2 to 4-fold increase in intrinsic antioxidant enzyme activities, thereby enabling highly efficient scavenging of reactive oxygen species (ROS). In vitro, platelet membrane camouflage increased neutrophil-associated uptake to 98.6%, while in vivo imaging demonstrated enhanced periodontal accumulation and prolonged retention. This targeted catalytic system effectively disrupts the ROS-neutrophil extracellular traps (NETs) amplification loop, suppresses inflammatory bone loss, and improves systemic metabolic parameters. This work demonstrates that a hetero-coordinated high-valence nano-mosaic, engineered through the rational repurposing of guanidine compounds and augmented by biomimetic targeting, offers a powerful therapeutic strategy for ameliorating diabetic periodontitis.
Helical quaternary amine polypeptide programs membrane stress to drive immunogenic cell death and cytosolic gene delivery for cancer immunotherapy.
Lee S, Jiao A, Park H … +12 more , Hong KH, Ha J, Nam H, Kim S, Kim S, Jeong SD, Lee D, Ha SJ, Yun CO, Lee YK, Yoon AR, Kim YC
Biomaterials · 2026 May · PMID 42229304 · Publisher ↗
Nanomaterials can shape antitumor immunity; however, the design rules that link molecular features to immune outcomes remain unclear. Here, we demonstrate that helical polypeptides with quaternary amine sidechains physic...
Nanomaterials can shape antitumor immunity; however, the design rules that link molecular features to immune outcomes remain unclear. Here, we demonstrate that helical polypeptides with quaternary amine sidechains physically disrupt phospholipid membranes, triggering the release of damage-associated molecular patterns (DAMPs) and enabling cytosolic gene delivery. Screening various sidechain amines and using mechanistic assays with a racemic control identifies quaternary amines, along with helicity, as key factors in immune responses. Mechanistically, physical membrane disruption damages membrane-based organelles-including mitochondria, the endoplasmic reticulum, and endosomes-leading to immunogenic cell death and facilitating endosomal escape of nucleic acids. Guided by this mechanism, guanidinium substitution strengthened phosphate engagement and reduced the apparent cationic density, thereby improving polyplex stability and immune activation. In mouse models of melanoma and colon cancer, local transfection with a PD-L1 knockout plasmid using a helical polypeptide reduced tumor burden by 70-80% and boosted effector T cell-mediated immunity. These findings illustrate how sidechain chemistry and helicity affect immune activation, offering a non-viral platform for antitumor immune priming.
Multifunctional immunomodulator with cascade catalytic activities to reprogram endoplasmic reticulum stress-mediated immunosuppression for enhancing anti-tumor immunotherapy.
Jin XK, Pan T, Xu ZH … +8 more , Zhang SM, Chen H, Wang YZ, Yan X, Dai JJ, Cheng SX, Liu CJ, Zhang XZ
Biomaterials · 2026 May · PMID 42229303 · Publisher ↗
Endoplasmic reticulum (ER) stress has been identified as a critical regulator of cholesterol metabolism and tumor-derived extracellular vesicles (tEVs) secretion in tumor cells, which significantly influences TME composi...
Endoplasmic reticulum (ER) stress has been identified as a critical regulator of cholesterol metabolism and tumor-derived extracellular vesicles (tEVs) secretion in tumor cells, which significantly influences TME composition and impairs anti-tumor immune responses. Here, we develop a multifunctional immunomodulator (CPMR) that simultaneously targets cholesterol metabolism and tEVs secretion, thereby reprogramming the ER stress-mediated immunosuppression and enhancing anti-tumor immunotherapy. CPMR is constructed by co-loading cholesterol oxidase (ChOx) and Rab27a-shRNA plasmid into a copper-based metal-organic framework (MOF-199) coated with DSPE-PEG-RGD. In 4T1 tumor cells, CPMR demonstrates favorable glutathione peroxidase-mimicking, ChOx and peroxidase-like activities, initiating cascade catalytic reactions that disrupt the intracellular redox and metabolic homeostasis, further triggering acute ER stress. Simultaneously, silencing of Rab27a effectively inhibits tEVs-mediated cholesterol efflux. The resulting intracellular cholesterol accumulation serves as a substrate for subsequent ChOx-mediated oxidative reactions, forming a positive feedback loop that amplifies oxidative stress. These synergistic effects ultimately induce immunogenic cell death. Notably, the reduction in extracellular levels of cholesterol and tEVs effectively mitigates the ER stress-mediated immunosuppression, thereby potentiating immune responses. This study offers a promising strategy to harness and mitigate the subsequent effects of ER stress for the advancement of anti-tumor immunotherapy.
MOF-based nanoparticles enabling blood-brain barrier crossing for non-invasive selective sononeuromodulation in epilepsy.
Pan X, Zhu Y, Qi X … +4 more , Li S, Gao T, Wang C, Wang H
Biomaterials · 2026 May · PMID 42229302 · Publisher ↗
Epilepsy affects millions worldwide, with a significant proportion of patients exhibiting resistance to conventional pharmacological treatments, highlighting the urgent need for innovative, non-invasive therapeutic strat...
Epilepsy affects millions worldwide, with a significant proportion of patients exhibiting resistance to conventional pharmacological treatments, highlighting the urgent need for innovative, non-invasive therapeutic strategies. Traditional electrical neuromodulation methods, such as deep brain stimulation, are hindered by their invasiveness, limited spatial precision, and associated risks of infection. In this study, we develop an ultrasound (US)-activated piezoelectric nanoparticle platform (PUANPs), based on a metal-organic framework, to enable precise and non-invasive neuromodulation for epilepsy management. Upon US stimulation, PUANPs convert mechanical energy into localized electrical signals, effectively modulating neuronal activity by enhancing inhibitory signaling and suppressing excitatory responses. Functionalized with brain-targeting ligands, PUANPs achieve efficient blood-brain barrier (BBB) penetration via receptor-mediated transport and US-induced cavitation. Furthermore, the incorporation of platinum nanoclusters enhances piezoelectric performance while concurrently attenuating neuroinflammation and oxidative stress in epileptic foci. By integrating neuromodulation, targeted BBB crossing, and microenvironmental regulation, PUANPs represent a multifunctional therapeutic approach that surpasses the limitations of conventional treatments and holds broad translational potential for epilepsy therapy.
Dopamine-modified TiCT MXene promotes supporting cell pluripotency and hair cell regeneration in cochlear organoid culture.
Zhang Y, Meng S, Ma X … +16 more , Li L, Zhang W, Zhang X, Qiao R, Xuan Y, Hu Q, Ma H, Wang Y, Liu X, Ma X, Sun J, Xue Y, Sun B, Kou B, Zhang M, Li XJ
Biomaterials · 2026 May · PMID 42229301 · Publisher ↗
Sensorineural hearing loss (SNHL), predominantly resulting from the irreversible loss of cochlear hair cells, remains a clinical challenge without effective treatments. Recently, neuromodulation strategies based on two-d...
Sensorineural hearing loss (SNHL), predominantly resulting from the irreversible loss of cochlear hair cells, remains a clinical challenge without effective treatments. Recently, neuromodulation strategies based on two-dimensional nanomaterials have shown regenerative potential, with MXene standing out due to its excellent electrical conductivity, biocompatibility, and modifiable surface properties. Hair cells (HCs) and supporting cells (SCs) originate from the same prosensory cells, with previous work showing that MXene (especially TiCT) incorporation in Matrigel can promote HCs formation with SCs in cochlear organoid culture. However, the MXene is prone to oxidation, losing the conductivity and catalytic activity of this material in Matrigel during HC regeneration. In this study, we modified MXene with dopamine (DA-MXene) that mimics neurotransmitter functions to promote HC regeneration. We found that DA-MXene significantly enhanced the proliferation and survival of SCs in organoid culture. HC formation was also upregulated in DA-MXene treated cochlear explant culture compared with MXene samples. Mechanistic studies indicated that DA-MXene further activated signaling pathways that regulate pluripotency of stem cells compared with MXene, which is vital for restoring the plasticity of SCs. Collectively, this work proposes an innovative nanomaterial-based approach that combines chemical modification and electroactive stimulation, offering a promising strategy for regenerating HCs in SNHL.
Ala-Ce@Ce6 hybrid supramolecular nanozyme for oxygen self-supplying hypoxia photodynamic therapy.
Li C, Yang X, Xiang C … +8 more , Jiang T, Liu Y, Xiang J, Zhang P, Xu Y, Cai L, Gong P, Wang X
Biomaterials · 2026 May · PMID 42229300 · Publisher ↗
The efficacy of photodynamic therapy (PDT) is often hindered by factors such as the poor bioavailability of photosensitizers, insufficient oxygen levels, and the elevated presence of glutathione (GSH) and hypoxia-inducib...
The efficacy of photodynamic therapy (PDT) is often hindered by factors such as the poor bioavailability of photosensitizers, insufficient oxygen levels, and the elevated presence of glutathione (GSH) and hypoxia-inducible factor 1-alpha (HIF-1α) in tumor cells. To address these challenges, a controlled supramolecular assembly approach was explored to construct uniform cerium oxide nanoparticles, denoted Ala-Ce@Ce6. Specifically, water-soluble alanine-cerium clusters were constructed using natural l-alanine as the ligand. Subsequently, these clusters are subjected to self-assembly using the photosensitizer Chlorin e6 under ice-bath and ultrasonication conditions, yielding uniform nanoparticles with favorable water solubility. This nanostructure not only enhances the delivery efficiency of Ce6 but also confers dual functionalities, namely reacting with hydrogen peroxide (HO) to simultaneously generate oxygen and deplete GSH. In vivo, the reaction with endogenous HO produces O, thereby alleviating hypoxia and lowering HIF-1α expression. Additionally, Ala-Ce@Ce6 reduces the levels of GSH, downregulates Glutathione Peroxidase 4 to induce ferroptosis, and releases Ce6 upon laser irradiation to boost reactive oxygen species generation and suppress tumor growth, demonstrating strong clinical potential for use in PDT.
Stealth red blood cells with broad-spectrum antigenic shielding for transfusion therapy in antibody-mediated hemolytic anemia.
Zhang Y, Huang Y, Yang Z … +6 more , Liao Z, Li S, Zhong M, Ming X, Gao Y, Wang B
Biomaterials · 2026 May · PMID 42229299 · Publisher ↗
Red blood cell (RBC) transfusion is a cornerstone of life-sustaining therapy, yet it is profoundly challenged in autoimmune hemolytic anemia (AIHA). In this disorder, a diverse array of autoantibodies targets both the au...
Red blood cell (RBC) transfusion is a cornerstone of life-sustaining therapy, yet it is profoundly challenged in autoimmune hemolytic anemia (AIHA). In this disorder, a diverse array of autoantibodies targets both the autologous and transfused RBCs, leading to their rapid clearance. This limitation is especially severe during hemolytic crises, rendering conventional transfusion ineffective and eliminating a critical therapeutic option. To overcome this, we developed a biocompatible strategy by utilizing a microbial transglutaminase that first anchors to the RBC membrane and then crosslinks a polysialic acid (PSA) network onto the cell surface. This created an immunologically inert shield that broadly masks surface antigens from pathogenic antibodies. Crucially, this "stealth" modification preserved the RBCs' native biological functions, including essential gas exchange, while conferring robust resistance to antibody-mediated hemolysis. In vitro, the engineered RBCs were protected from antibody binding and macrophage phagocytosis. This protection translated to a significantly prolonged circulation time in AIHA murine models and demonstrated excellent biocompatibility in an allogeneic transfusion setting. Our findings underscore the significant potential of this platform to enable effective, life-saving transfusion therapies for AIHA and other antibody-mediated disorders.
Chiral D-peptide composite hydrogels enable sustained RepSox delivery and antifibrotic remodeling after myocardial infarction.
Liu M, Huang L, Guo W … +7 more , Luo Q, Bai L, Zhang S, Wu Y, Hu C, Wu J, Wang Y
Biomaterials · 2026 May · PMID 42225054 · Publisher ↗
Persistent oxidative stress and profibrotic signaling after myocardial infarction (MI) contribute to adverse ventricular remodeling. Although peptide hydrogels show potential for MI treatment, conventional L-peptides are...
Persistent oxidative stress and profibrotic signaling after myocardial infarction (MI) contribute to adverse ventricular remodeling. Although peptide hydrogels show potential for MI treatment, conventional L-peptides are susceptible to rapid enzymatic degradation, which can lead to premature drug release and limited therapeutic durability. Here, we developed a chiral composite hydrogel (D Gel@RepSox) by combining self-assembling D-enantiomeric antioxidant peptides with RepSox-loaded nanoparticles. Compared with the corresponding L-peptide hydrogel, the D-peptide system showed greater proteolytic resistance, prolonged retention, and more sustained drug release. The peptide hydrogel also retained intrinsic bioactivity and contribute to regulation of the local microenvironment after MI. Accordingly, D Gel@RepSox exerted therapeutic effects during both the inflammatory and remodeling phases. At day 28 after MI, treatment with D Gel@RepSox was associated with improved cardiac function, a 34.0% reduction in collagen volume fraction, and increases in ejection fraction (EF) and fractional shortening (FS) of 33.5% and 27.4%, respectively. Transcriptomic, gene, and protein level analyses further suggested that these effects may be associated, at least in part, with suppression of profibrotic signaling, including the TGF-β/Smad3 pathway. Together, these findings support peptide chirality engineering as a strategy to improve hydrogel stability and enable sustained antifibrotic drug delivery for myocardial repair.
PPS03 triggers cancer-selective necroptosis in hepatocellular carcinoma via macropinocytosis-dependent ROS overload.
Choi KH, Park J, Yoon H … +5 more , Park K, Hur C, Kim SM, Park KC, Lim JH
Biomaterials · 2026 May · PMID 42218110 · Publisher ↗
Hepatocellular carcinoma (HCC) may be curable when detected and at an early stage. However, recurrence and metastatic progression occur frequently following therapeutic intervention, leading to treatment-refractory disea...
Hepatocellular carcinoma (HCC) may be curable when detected and at an early stage. However, recurrence and metastatic progression occur frequently following therapeutic intervention, leading to treatment-refractory disease. Such refractory HCCs are resistant to systemic therapies, facilitating metastatic dissemination and disease relapse, highlighting the need for alternative therapeutic strategies. To address the limited efficacy of available systemic therapies, we developed a new polyaspartic acid (PASP) based polymer-metal complex, PPS03, with well-defined physicochemical properties, including nanoscale size distribution and stable metal incorporation. We showed that PPS03 induced cancer-selective necroptosis through preferential macropinocytic uptake in patient-derived metastatic HCC models. Specifically, PPS03 promoted necroptotic cell death by stimulating an accumulation of the mitochondrial reactive oxygen species (ROS) via selective intratumoral elevation of hydrogen peroxide (HO). Mechanistically, PPS03 exploited differential macropinocytic activity, which is high in tumor cells but very low in normal hepatocytes. This activity enabled selective uptake of PPS03-bound selenomethionine and ferrous iron, amplifying HO-mediated mitochondrial ROS production within cancer cells. Consistent with this selectivity, PPS03 exhibited minimal cytotoxicity in normal THLE-2 hepatocytes, while it strongly suppressed the viability of HCC cells. Notably, in patient-derived cisplatin-resistant metastatic HCC models, PPS03 significantly inhibited tumor growth both in vitro and in vivo whereas cisplatin showed no significant efficacy. Furthermore, PPS03 reduced stem-like tumor features, as evidenced by decreased sphere formation and reduced CD133 expression, likely reflecting preferential elimination of stem-like tumor cells. Collectively, these findings present PPS03 as a polymer-metal complex that selectively induces necroptosis in refractory HCC with minimal off-target toxicity, providing a potential therapeutic strategy to address drug resistance in advanced disease.
Dual-pathway blockade overcomes ferroptosis resistance in pancreatic ductal adenocarcinoma via a CD133-targeted manganese-porphyrin theranostic nanoplatform.
Xu K, Xie C, Wu R … +9 more , Luo J, Ye Y, Zhang Y, Song M, Xue M, Zeng A, Ren W, Wu A, Wang J
Biomaterials · 2026 May · PMID 42218109 · Publisher ↗
Ferroptosis has emerged as a promising strategy for treating refractory malignancies such as pancreatic ductal adenocarcinoma (PDAC), but its efficacy is limited by multilayered resistance, including classical tumor-intr...
Ferroptosis has emerged as a promising strategy for treating refractory malignancies such as pancreatic ductal adenocarcinoma (PDAC), but its efficacy is limited by multilayered resistance, including classical tumor-intrinsic pathways and a recently identified cancer-associated fibroblast (CAF) bypass mediated by the TGFβ1-Cys-GSH axis. Most studies have focused on cancer cell-intrinsic mechanisms, leaving ferroptosis-based therapy for PDAC suboptimal. To address this challenge, we propose a dual-pathway blockade that simultaneously targets both the intrinsic cancer cell pathway and the CAF-mediated exogenous pathway. We developed a multifunctional theranostic nanoplatform (MEC), consisting of a manganese-porphyrin metal-organic framework (MOF) loaded with Erastin and surface-modified with an anti-CD133 monoclonal antibody (CD133 mAb) for targeted delivery. In combination with Repsox, MEC disrupts the cysteine exchange cascade between cancer cells and fibroblasts, thereby depleting intracellular glutathione (GSH), enhancing reactive oxygen species (ROS) generation through TCPP-mediated sonodynamic and Mn-driven Fenton-like reactions, and inducing lipid peroxidation-dependent ferroptosis in PDAC cells. Moreover, MEC offers dual-modality magnetic resonance-fluorescence imaging to noninvasively visualize intratumoral GSH dynamics, enabling treatment optimization and precise therapeutic response assessment. Collectively, this study establishes a comprehensive strategy to overcome ferroptosis resistance in pancreatic cancer and introduces a multifunctional theranostic nanoplatform with potential for effective PDAC management.
Attenuating chemotherapy-induced nephrotoxicity while potentiating antitumor efficacy by transforming a Janus drug into dual-targeting carbonized polymer dots.
Zou W, Shang C, Hao Z … +6 more , Li N, Mi X, Yan X, Li X, Du Y, Wang H
Biomaterials · 2026 May · PMID 42218108 · Publisher ↗
Chemotherapy-induced acute kidney injury (AKI) remains a major clinical challenge because existing renoprotective agents often compromise the antitumor efficacy of chemotherapeutics. To address this limitation, we transf...
Chemotherapy-induced acute kidney injury (AKI) remains a major clinical challenge because existing renoprotective agents often compromise the antitumor efficacy of chemotherapeutics. To address this limitation, we transformed apigenin, a natural flavonoid with Janus bioactivities, into bioactive carbonized polymer dots (Api-CPDs) via a one-step carbonization process. The resulting Api-CPDs exhibit markedly high hydrophilicity, prolonged retention in the body, and, most importantly, preferential accumulation in both renal tissues and tumors. Mechanistically, Api-CPDs potently activate the Nrf2/HO-1 pathway and promote mitophagy, thereby shielding kidneys from cisplatin-induced apoptosis. Beyond conferring renoprotection, Api-CPDs enhance the antitumor efficacy of chemotherapeutics by modulating the p53 pathway. Collectively, this study demonstrates that transforming a Janus drug into bioactive carbonized polymer dots effectively overcomes the inherent limitations of small-molecule flavonoids, including poor aqueous solubility, rapid clearance, and lack of target specificity, enabling concurrent mitigation of chemotherapy-induced nephrotoxicity and potentiation of antitumor efficacy.
Dual-functional poly(disulfide) enables "Once-and-for-all" atherosclerosis therapy via precision hepatocyte base editing.
Zhang X, Gao S, Chen D … +5 more , Wang H, Zuo M, Wang L, Zhang QW, Wang R
Biomaterials · 2026 May · PMID 42214211 · Publisher ↗
CRISPR-based base editors hold transformative potential for genetic medicine, but their clinical translation is hampered by the need for cell-specific delivery, efficient cytosolic release, and durable activity. Here, we...
CRISPR-based base editors hold transformative potential for genetic medicine, but their clinical translation is hampered by the need for cell-specific delivery, efficient cytosolic release, and durable activity. Here, we report a dual-functional poly(disulfide) that simultaneously achieves both hepatocyte-specific targeting and direct cytosolic delivery of adenine base editors (ABEs). By displaying galactose ligands for binding to asialoglycoprotein receptors (ASGPRs) on hepatocytes, our polymer enables specific recognition of hepatocytes. Crucially, the poly(disulfide) backbone then facilitates direct cytosolic delivery via thiol-disulfide exchange, bypassing endosomal entrapment. This dual-function system mediates efficient ABEs delivery to hepatocytes, resulting in durable editing of the ANGPTL-3 gene after a single administration. In a mouse model of atherosclerosis, this one-dose treatment produced sustained reductions in low-density lipoprotein cholesterol and significantly attenuated plaque formation. To our knowledge, this represents the first successful application of base editing for the effective prevention and treatment of atherosclerosis with a single-dose. Our work establishes a "once-and-for-all" atherosclerosis treatment that creates a transformative platform for precision genome medicine in atherosclerosis and other metabolic diseases.
A Stability-oriented heavy-atom-free Nile red photosensitizer via heterocyclic thionation and D-A intensification for ferro-pyroptosis photodynamic immunotherapy.
Qin R, Li Y, Qiu T … +9 more , Wang R, Li Y, Shi S, Liu Y, Zhou D, Fan J, Zeng X, Sun W, Peng X
Biomaterials · 2026 May · PMID 42214210 · Publisher ↗
Nile Red derivatives typically suffer from limited intersystem crossing (ISC) efficiency in photodynamic therapy. Conventional ISC-enhancement strategies, such as heavy-atom incorporation and carbonyl thionation, often c...
Nile Red derivatives typically suffer from limited intersystem crossing (ISC) efficiency in photodynamic therapy. Conventional ISC-enhancement strategies, such as heavy-atom incorporation and carbonyl thionation, often compromise increased dark toxicity, shortened triplet lifetimes, or poor photostability. Herein, we report a heavy-atom-free molecular design strategy for Nile Red-based photosensitizers (PSs) that overcomes these limitations. The optimized PSs, NRS-N-Me, synergistically integrates heterocyclic sulfur incorporation with donor-acceptor (D-A) system intensification. Sulfur is introduced into the heterocyclic N-O framework, enhancing spin-orbit coupling (SOC) through orbital mixing while avoiding labile thione motifs. Concurrently, replacement of the native naphthol unit with a methylated quinolinium acceptor strengthens the intramolecular donor-acceptor (D-A) push-pull effect. This dual engineering minimizes singlet-triplet energy gap (ΔE<0.1 eV) and enables cascade ISC via higher triplet states (T/T), affording a high singlet oxygen quantum yield of 25.4% with red-shifted absorption. Mitochondrial accumulation of cationic NRS-N-Me enables localized Type I/II ROS generation, triggering synergistic ferro-pyroptosis cell death that overcomes apoptosis resistance and elicits potent immunogenic cell death (ICD). In vivo, liposomal NRS-N-Me achieves 90.09% tumor inhibition and suppresses metastasis in a 4T1 tumor model. This work establishes a stability-oriented, heavy-atom-free design paradigm for Nile Red-based PSs by integrating D-A optimization with heterocyclic N-O framework thionation, which offers a general platform for next-generation photodynamic immunotherapy.
O-releasing microneedle platform eradicates drug-resistant bacterial biofilm via metabolic interference and innate immune reactivation.
Liu S, Zhang Z, Ge Z … +6 more , Teng R, Chen R, Qin J, Sun M, Du J, Fan Z
Biomaterials · 2026 May · PMID 42214209 · Publisher ↗
Biofilm-associated infections pose formidable clinical challenges due to their complicated microenvironment characterized by dense extracellular polymeric substances (EPS), hypoxia, and excessive HO. While microneedles c...
Biofilm-associated infections pose formidable clinical challenges due to their complicated microenvironment characterized by dense extracellular polymeric substances (EPS), hypoxia, and excessive HO. While microneedles can mechanically penetrate biofilms, their efficacy is limited by poor diffusion of antibacterial agents through EPS and secondary infection resulting from escaping planktonic bacteria. Herein, we proposed an oxygen-powered microneedle (FeCN@MN) that synergistically eradicates biofilms through a dual mechanism: ferroptosis-like death-mediated bacterial killing and neutrophil reactivation. The microneedle utilizes sodium percarbonate (SPO) particles that react with interstitial fluid to generate O bubbles, which propel the loaded FeS-decorated carbon nanospheres (FeCN) to disperse throughout biofilms. Moreover, the FeCN@MN can reactivate neutrophils to scavenge planktonic bacteria escaping from biofilm disintegration through enhanced chemotaxis and respiratory burst, further inhibiting potential recurrence of infection. In vitro experiment reveals that iron overload disrupts amino acid metabolism and peroxide accumulation, promoting bacterial ferroptosis-like death. Furthermore, neutrophil functional tests show enhanced chemotaxis and killing ability to MRSA bacteria. In MRSA biofilm-infected diabetic wound model, FeCN@MN significantly dismantles biofilms, and effectively eliminates infections. In conclusion, this two-stage therapeutic approach combining bacterial metabolic interference with immune response reactivation provides a promising strategy in eradicating drug-resistant bacterial biofilm-associated infections.
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