The management of inflammatory bowel disease (IBD) continues to pose a substantial clinical obstacle, owing to the intricate nature of its pathophysiology. Targeted micro/nano drug delivery systems, which can exploit the...The management of inflammatory bowel disease (IBD) continues to pose a substantial clinical obstacle, owing to the intricate nature of its pathophysiology. Targeted micro/nano drug delivery systems, which can exploit the synergistic effects of multiple components, represent a promising therapeutic strategy. In this study, we developed a colon-targeted co-delivery system based on hydrogel microspheres (CCB@HMs) using droplet microfluidics, serving as a versatile micro/nano platform for IBD therapy. This system enables the targeted delivery of budesonide (BDS) while leveraging curcumin (Cur) and inulin as both drug carriers and antioxidants, thereby compensating for the limited reactive oxygen species (ROS)-scavenging capacity of BDS and achieving synergistic therapeutic effects. In vitro and in vivo evaluations demonstrated that CCB@HMs efficiently deliver drugs to inflamed colonic tissues, providing prolonged retention and sustained release. The microspheres effectively scavenge ROS, alleviate oxidative stress, modulate intestinal immunity, repair the epithelial barrier, and restore gut homeostasis. Collectively, these results confirm the synergistic therapeutic effects of CCB@HMs in a murine colitis model, positioning them as a promising targeted and multifunctional oral delivery strategy for IBD.
Reactive oxygen species (ROS)-catalytic artificial enzymes have emerged as a promising way to combat malignant tumors, yet their efficacy remains constrained by tumor hypoxia, oxygen dependence, and robust antioxidant de...Reactive oxygen species (ROS)-catalytic artificial enzymes have emerged as a promising way to combat malignant tumors, yet their efficacy remains constrained by tumor hypoxia, oxygen dependence, and robust antioxidant defenses. Herein, we report the de novo design of a bioinspired manganese@gold cluster-coordinated covalent organic frameworks-based artificial metalloenzymes (AuC@SCOF-Mn) with efficient cascade biocatalysis and amplified systemic stimulation to combat malignant tumor metastasis. Experimental and theoretical results demonstrate that the AuC@SCOF-Mn heterojunction architecture accelerates electron transfer and drives oxygen-independent type I photoreactions under low-dose light irradiation, which confer dual-enzyme-like activities to catalyze glucose-to-HO-to-ROS conversion and deplete intracellular glutathione. The multiple functionalities not only disrupt redox homeostasis to amplify ROS accumulation but also elicit potent tumoricidal effects through mitochondrial dysfunction and DNA damage. Beyond direct cytotoxicity, AuC-SCOF-Mn effectively reprograms the tumor microenvironment by enhancing cytokine-cytokine receptor interactions, thereby promoting dendritic cell antigen presentation, CD8T cell activation, and NK cell infiltration. Correspondingly, AuC@SCOF-Mn demonstrates potent tumor suppression and long-term inhibition of tumor recurrence in vivo. When combined with checkpoint therapy, it further amplifies systemic antitumor responses and inhibits malignant tumor lung metastasis. We believe the innovative design of ROS-catalytic, photo-activable artificial enzymes will open a promising avenue for treating malignancies.
Wang S, Sun W, Yoo J
… +8 more, Chen G, Kim D, Liu LQ, Jin DW, Kim S, Yin S, Wang KN, Kim JS
Biomaterials
· 2026 Jun · PMID 42400992
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Triple-negative breast cancer (TNBC) is recognized as one of the most aggressive breast cancer subtypes, with poor responsiveness to current immunotherapies primarily due to its strongly immunosuppressive tumor microenvi...Triple-negative breast cancer (TNBC) is recognized as one of the most aggressive breast cancer subtypes, with poor responsiveness to current immunotherapies primarily due to its strongly immunosuppressive tumor microenvironment (TME). Here, we report a multifunctional nanoplatform, AIF NPs that integrates near-infrared (808 nm) photothermal therapy (PTT), ferroptosis induction, and immunosuppressive axis blockade into a feedback-amplified therapeutic system. The silicon-based photothermal agent IR1024 demonstrates an exceptionally high photothermal conversion efficiency of 93.4%, enabling efficient PTT under clinically relevant irradiation. Ferroptosis-induced lipid peroxidation downregulates HSP90, attenuating thermo-resistance; PTT-generated heat accelerates fatty acid oxidation and lipid peroxidation, further amplifying ferroptosis. The resulting immunogenic cell death (ICD) promotes dendritic cell maturation and CD8 T cell infiltration, while AB928 alleviates adenosine-mediated immunosuppression, allowing ICD-driven immunity to be sustained. This immune activation enhances IFN-γ production, which cooperates with arachidonic acid (AA) to downregulate SLC7A11 and further reinforce ferroptosis, thus completing a self-reinforcing PTT-ferroptosis-immunity loop. Experimental results demonstrate that AIF NPs effectively rewires immunologically "cold" TNBC into a responsive "hot" phenotype, achieving over 90% tumor growth inhibition in a 4T1 murine model with minimal systemic toxicity. These findings highlight how feedback-driven coordination of cell death and immunity can be strategically leveraged to address therapeutic bottlenecks in TNBC.
Wang X, Wen Y, Sun K
… +10 more, Liu H, Wang C, Xu M, Chen D, Li Y, Chu C, Xue F, Zhao Y, Bai J, Li J
Biomaterials
· 2026 Jun · PMID 42398423
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Diabetic wounds are characterized by persistent infection, excessive oxidative stress, and impaired healing. Conventional dressings often lack autonomous adhesion and wound-closure capabilities, and fail to balance essen...Diabetic wounds are characterized by persistent infection, excessive oxidative stress, and impaired healing. Conventional dressings often lack autonomous adhesion and wound-closure capabilities, and fail to balance essential antimicrobial and anti-inflammatory properties. Inspired by the sucker morphology and thermo-responsive behavior of the octopus, this study developed a Three-Dimensional (3D)-printed, photosensitive/thermosensitive dual-responsive poly(N-isopropylacrylamide) (PNIPAM)/gelatin hydrogel dressing. The hydrogel was functionalized with mesoporous MgO nanoparticles coated with self-assembled curcumin and polydopamine (MCP NPs). Under near-infrared (NIR) irradiation, the hydrogel achieved robust tissue adhesion (∼2.3 N cm) facilitated by biomimetic sucker structures and integrated adhesive groups. The MCP NPs, stabilized by π-π stacking and electrostatic interactions, enabled sequential reactive oxygen species generation and scavenging. During the repair process, NIR-triggered controllable contraction allowed the hydrogel to actively close wounds, exert potent antibacterial effects, and promote extracellular matrix remodeling through the activation of the Hippo and Fibroblast Growth Factor (FGF) signaling pathways. By integrating antioxidant activity, bioactive Mg ions release, and photothermal therapy, the hydrogel effectively inhibited macrophage pyroptosis and restored the mitochondrial membrane potential. Furthermore, it reprogrammed macrophages from the metabolic and immune perspectives by modulating the glycolysis/gluconeogenesis and Interleukin-10 (IL-10) pathways, while suppressing the NF-κB pathway. In diabetic rat models, the hydrogel significantly accelerated angiogenesis and re-epithelialization, achieving wound closure four days earlier than the untreated group. Overall, this study presents a promising strategy for the effective clinical management of infected diabetic wounds.
Wang W, Fan C, Xu H
… +9 more, Jiang J, Liang X, Wang T, Wang W, Ge G, Li H, Wang Q, Sun H, Geng D
Biomaterials
· 2026 Jun · PMID 42398422
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Intervertebral disc degeneration (IVDD) is characterized by inflammation-driven pyroptosis of nucleus pulposus (NP) cells. While oligonucleotide-based gene therapy holds promise for precision intervention, its clinical t...Intervertebral disc degeneration (IVDD) is characterized by inflammation-driven pyroptosis of nucleus pulposus (NP) cells. While oligonucleotide-based gene therapy holds promise for precision intervention, its clinical translation is hindered by inefficient cellular delivery and rapid lysosomal degradation. Here, we identified miRNA-223 as a pivotal regulator of IVDD, where its overexpression mitigated the inflammatory extracellular matrix (ECM) metabolic imbalance in NP cells in vitro. To overcome delivery barriers in vivo, we engineered an injectable multifunctional cell-penetrating peptide (CPP), R9-DOPA-DBCO, which spontaneously self-assembles with azido-modified miRNA-223 via bioorthogonal click chemistry to form nanocomplexes (R9-DOPA-miRNA223). These nanoparticles not only exhibited superior cell membrane penetration and lysosomal escape capabilities but also exhibited significant therapeutic efficacy in mitigating NP cell pyroptosis and restoring ECM metabolic homeostasis via the MKNK2/eIF4E/NOD-like signaling pathway, concomitantly attenuating IVDD progression in rat models. This direct and efficient delivery strategy not only has transformative potential for IVDD therapy but also broadens the conceptual and methodological framework for precision miRNA-based therapeutics.
Cheng A, Yu Y, Ding J
… +4 more, Sun S, Li P, Sun R, Fan K
Biomaterials
· 2026 Jun · PMID 42391990
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Acute radiation proctitis (ARP) is a common complication of pelvic radiotherapy driven by direct DNA damage and excessive reactive oxygen species (ROS) induced oxidative stress. Currently, effective clinical treatments t...Acute radiation proctitis (ARP) is a common complication of pelvic radiotherapy driven by direct DNA damage and excessive reactive oxygen species (ROS) induced oxidative stress. Currently, effective clinical treatments that can systematically intervene in ARP are lacking. In this study, we developed an injectable, multicenter cascade nanozyme gel (Ce-MnCo LDH gel) for intrarectal administration to combat radiation-induced intestinal injury. By atomically integrating cerium (Ce) into the lattice of manganese-cobalt layered double hydroxides (MnCo LDH), we constructed a complex multicenter electron transfer network, endowing the nanozyme with potent, broad-spectrum catalase-, superoxide dismutase-, and glutathione peroxidase-like activities that effectively neutralize various ROS. Ce-MnCo LDH gel exhibited good stability and local retention capacity, effectively alleviated radiation-induced oxidative damage, reduced DNA damage, protected mitochondrial function, and inhibited NF-κB-mediated inflammatory signaling. In the ARP rat model, intrarectal administration of Ce-MnCo LDH gel effectively alleviated radiation-induced injury. This platform restored the expression of tight junction proteins (ZO-1 and Claudin-3) in epithelial cells, repaired the integrity of the intestinal epithelial barrier, and remodeled the immune microenvironment in damaged areas by regulating inflammatory factors. In summary, this study provides a promising therapeutic strategy for radiation-induced intestinal injury and other oxidative inflammatory diseases.
Chen Z, Ramanujam V, Maricar S
… +8 more, Liu Y, Huang C, Wong L, Shebanova A, Ma Z, Sun Y, Czarny B, Miserez A
Biomaterials
· 2026 Jun · PMID 42391989
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Immune checkpoint blockade targeting the PD-1/PD-L1 axis shows limited efficacy in microsatellite-stable (MSS) colorectal cancer (CRC), primarily due to an immunosuppressive tumor microenvironment (TME) and insufficient...Immune checkpoint blockade targeting the PD-1/PD-L1 axis shows limited efficacy in microsatellite-stable (MSS) colorectal cancer (CRC), primarily due to an immunosuppressive tumor microenvironment (TME) and insufficient T-cell activation. Here, we report a peptide coacervate-mediated siRNA delivery platform that enables coordinated gene silencing of PD-1 in T-cells and PD-L1 in tumor cells to enhance CRC immunotherapy. HBpep-SP coacervates (HCs) were functionalized with anti-CD3 antibodies to generate targeted coacervates (THCs), enabling efficient T-cell-targeted delivery of PD-1 siRNA, robust PD-1 knockdown, and enhanced T-cell effector function, as indicated by increased IL-2 and IFN-γ production. In parallel, HCs efficiently delivered PD-L1 siRNA into CRC cells, achieving significant PD-L1 knockdown. Dual checkpoint silencing in a co-culture system of T-cells and CRC cells synergistically enhanced T-cell proliferation and activation, leading to increased tumor cell apoptosis. Importantly, in a murine MSS CRC model, intratumoral co-administration of siPD-1@THC and siPD-L1@HC simultaneously suppressed PD-1 and PD-L1 expression within the TME, increased intratumoral T-cell abundance, and elevated pro-inflammatory cytokine levels, resulting in restored antitumor immunity and significant tumor growth inhibition. Collectively, this peptide coacervate-based dual-checkpoint RNA interference strategy provides a promising approach for advancing T-cell-mediated immunotherapy in MSS colorectal cancer.
Cancer sonodynamic therapy (SDT) has attracted increasing attention in recent years due to its superior spatiotemporal control over chemotherapy and deeper penetration than photodynamic therapy (PDT). However, ultrasound...Cancer sonodynamic therapy (SDT) has attracted increasing attention in recent years due to its superior spatiotemporal control over chemotherapy and deeper penetration than photodynamic therapy (PDT). However, ultrasound (US) is difficult to be precisely focused on tumours. Hence, sonosensitizers that diffuse into healthy tissues may be accidently excited to generate reactive oxygen species (ROS), resulting in off-target toxicity. More importantly, current sonosensitizers exhibit high toxicity and are not biodegraded after SDT, potentially leading to systemic toxicity. Here, we developed a chitosan-oxalate hydrogel (Chi-OA) that is only stable in tumour for tumour-confined SDT. Without the need to load any traditional sonosensitizers, the hydrogel relied on the intrinsically present oxalate ions to generate ROS under US irradiation. Following intratumoural injection, the hydrogel was stable and exhibited high ROS generation yield in tumour microenvironment (TME) under US irradiation. In contrast, it degraded in healthy tissues and exhibited a lower ROS yield. This enabled SDT to be confined within the tumour and allowed the hydrogel to degrade and be cleared after SDT.
Li W, Wang X, Fu Y
… +6 more, Xie J, Cao J, Yu L, Miao R, Ou M, Mei L
Biomaterials
· 2026 Jun · PMID 42385493
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Inflammatory bowel disease (IBD) is characterized by chronic intestinal inflammation driven by intestinal barrier disruption, immune dysregulation, and microbiota imbalance. Barrier dysfunction not only aggravates intest...Inflammatory bowel disease (IBD) is characterized by chronic intestinal inflammation driven by intestinal barrier disruption, immune dysregulation, and microbiota imbalance. Barrier dysfunction not only aggravates intestinal inflammation but also promotes metabolic liver diseases, such as non-alcoholic steatohepatitis (NASH), through the gut-liver axis. However, current IBD therapies mainly target intestinal oxidative stress and inflammation, with limited efficacy, while NASH treatments focus on the liver, and interventions targeting the gut-liver axis remain limited. Here, we developed a synergistic quadruple intestinal barrier repair system, termed PGaA Gel, based on an inulin hydrogel loaded with gallium-based mesoporous polydopamine nanoparticles (MPDA-Ga) and L-alanyl-l-glutamine (ALG). PGaA Gel was designed to simultaneously restore the physical, chemical, immune, and microbial barriers of the intestine. MPDA-Ga effectively scavenged reactive oxygen species and inhibited pathogenic bacteria, while ALG promoted epithelial regeneration and mucin production. In addition, inulin enhanced intestinal retention and acted as a prebiotic to produce short-chain fatty acids, thereby reinforcing immune tolerance. In mouse models, PGaA Gel exhibited superior efficacy in restoring multidimensional intestinal barrier integrity and significantly alleviated IBD symptoms compared with single-component treatments. Importantly, PGaA Gel also repaired intestinal barrier dysfunction associated with NASH, reduced lipopolysaccharide translocation via the gut-liver axis, and mitigated hepatic inflammation and lipid accumulation. These findings highlight comprehensive intestinal barrier repair as an effective therapeutic strategy for IBD and gut-liver axis-related liver diseases.
Yang S, Guo L, Ou X
… +6 more, Yao J, Zheng J, Zheng M, Jin G, Zhou S, Tang BZ
Biomaterials
· 2026 Jun · PMID 42385492
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Developing NIR-II AIEgens with high fluorescence efficiency offers significant potential to revolutionize disease diagnosis and monitoring. However, existing designs largely rely on twisted donor-acceptor, donor-π-bridge...Developing NIR-II AIEgens with high fluorescence efficiency offers significant potential to revolutionize disease diagnosis and monitoring. However, existing designs largely rely on twisted donor-acceptor, donor-π-bridge, or acceptor-π-bridge motifs. Although twisted dual-acceptor architectures provide a fresh paradigm, reliance on a single twisted component has limited structural diversity and capped performance gains, necessitating innovative design philosophy. Here, we introduce a dual-twisted strategy that integrates two distinct types of twisted elements, namely a twisted dual-acceptor and a distorted acceptor-π bridge, within a single fluorophore. Compared with its single-twist analogue, the dual-twisted 2TT-o2BBTD exhibits not only an enhanced AIE effect but also a remarkable improvement in relative quantum yields (QY). Specifically, its relative QY is 7.6 times higher in solution and 27.5 times higher in the aggregate state than that of the control molecule. Mechanistic studies reveal that the dual-twisted design strengthens intermolecular interactions, mitigates intramolecular motions, and weakens nonradiative decay, thereby drastically boosting fluorescence emission. Leveraging these advantages, 2TT-o2BBTD NPs enable high-quality visualization of whole-body vasculature, the mesenteric system, tumor resection process, and cerebrovascular network. Collectively, this work presents the first evidence that the dual-twisted tactic could serve as a new design direction for the AIE development, delivering stronger packing, superior AIE effect, and improved bioimaging performance.
Lin P, Hu X, Tan X
… +10 more, Wang G, Jiang M, Zhang R, Li J, Liang C, Huo F, Li P, Zhu T, Tian W, Xie L
Biomaterials
· 2026 Jun · PMID 42385491
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In dental pulp regeneration, the ischemic microenvironment within the root canal severely compromises the survival and function of transplanted human dental pulp stem cells (hDPSCs). Here, we developed a PDMS-based core-...In dental pulp regeneration, the ischemic microenvironment within the root canal severely compromises the survival and function of transplanted human dental pulp stem cells (hDPSCs). Here, we developed a PDMS-based core-shell oxygen-glucose delivery platform (P-C@P-G) that continuously released oxygen and glucose for up to 40 and 29 days, respectively, while minimizing peroxide-associated cytotoxicity through diffusion-controlled regulation without the need for exogenous enzymes. Under oxygen-glucose deprivation (OGD, 0.1% O, glucose-free conditions) conditions, P-C@P-G improved cellular metabolic activity and enhanced hDPSC survival, proliferation, migration, and odontogenic differentiation. Compared with single-substrate supplementation, dual oxygen-glucose delivery produced greater improvements in hDPSC survival and differentiation. Transcriptomic and molecular analyses revealed alterations in TNF-α/NF-κB and Wnt/β-catenin signaling pathways following treatment. In vivo, P-C@P-G promoted pulp-like tissue regeneration, vascularization, and dentin sialophosphoprotein (DSPP) expression, resulting in greater pulp-like tissue formation and vascularization than the control group. Collectively, these findings demonstrated that sustained oxygen-glucose delivery effectively alleviated ischemia-associated metabolic insufficiency and revealed distinct contributions of oxygen and glucose to dental pulp regeneration.
Skrodzki D, Saha P, Molinaro M
… +8 more, Maher N, Krishnakumar S, Gunaseelan N, Moitra P, Dogan Z, Vigoya GC, Cho SH, Pan D
Biomaterials
· 2026 Jun · PMID 42385490
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A two-dimensional (2D) hafnium sulfide nanoplatelet (HfNP) platform with a phospholipid coating was developed to integrate physical radiosensitization with biochemical inhibition of DNA repair through an "amplify-and-arr...A two-dimensional (2D) hafnium sulfide nanoplatelet (HfNP) platform with a phospholipid coating was developed to integrate physical radiosensitization with biochemical inhibition of DNA repair through an "amplify-and-arrest" strategy. The high atomic number of hafnium gives HfNPs a large photoelectric cross-section, enhancing absorption of incident radiation and the generation of secondary electrons that amplify the locally deposited dose, with nanoparticle morphology presenting an opportunity to further increase electron escape. The lipid coating provides aqueous stability and high drug-loading capacity, enabling incorporation of a phospholipid-conjugated Mirin prodrug (proMirin) that is activated by tumor-associated pH and phospholipase A to suppress homologous recombination repair. Structural characterization confirmed crystalline 2D morphology, surface coating integrity, and efficient prodrug incorporation. In vitro and in vivo studies demonstrated enhanced radiosensitization, robust inhibition of RAD51-mediated repair, prolonged intratumoral retention plausibly driven by platelet-like geometry, and minimal systemic toxicity. These results establish HfNPs as a high-Z radiosensitizing platform that improves radiotherapeutic outcomes through both enhanced physical energy deposition and biochemical blockade of damage repair, with nanoplatelet dimensionality presenting an opportunity to further strengthen these effects.
Zhang P, Wu JC, Wang H
… +13 more, You HH, Wang DX, Jin JY, Duan HZ, Li MS, Li P, Wang K, Tong ZC, Guo PY, Wang Z, Zhao YB, Tang BZ, Hou DY
Biomaterials
· 2026 Jun · PMID 42372507
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Peptide-drug conjugates (PDC) have recently garnered substantial attention as promising strategies for targeted tumor therapy. However, the clinical efficacy of PDC is limited by poor membrane permeability and inherent l...Peptide-drug conjugates (PDC) have recently garnered substantial attention as promising strategies for targeted tumor therapy. However, the clinical efficacy of PDC is limited by poor membrane permeability and inherent lysosomal sequestration. Herein, we report an in-situ cascade assembled peptide-drug conjugate (ISCA-PDC) accomplished by integrating CXCR4-targeting cyclic peptide (Cyclo(DTyr-NMe-DOrn-Arg-2Nal-Gly)), a lysosomal-triggered assembled peptide linker (VEALYL) decorated with pH-sensitive moiety (cis-aconitic anhydride, CAA), and cytotoxic payload (camptothecin, CPT), to improve the tumor membrane permeability and realize lysosomal destabilization, ultimately enhancing the chemotherapy of bladder cancer. In the acidic microenvironment (pH 6.5) of the tumor, ISCA-PDC could first self-assemble into nanoparticles (NPs-PDC) after the hydrolysis of CAA and quickly enter the lysosome via CXCR4-mediated endocytosis to improve tumor membrane permeability. Following transformation into nanofibers (NFs-PDC) within lysosomes (pH 5.0), the permeability of the lysosomes was markedly enhanced, resulting in cathepsin B-induced apoptosis and CPT release. In addition, ISCA-PDC exhibited highly potent antitumor efficacy, which extended the overall survival of tumor recurrence model mice and led to the eradication and regression of T24-luc orthotopic xenograft mice. The concept of in-situ cascade-assembled PDC can be extended by conjugation with other chemotherapeutic agents, suggesting a generalizable strategy for nanotherapeutic enhancement in solid tumors.
Viola H, Carter H, Griffin K
… +13 more, Costa RM, McDonald R, Callow B, Gonzalez de Los Santos F, Panovich P, Carey S, Martinez M, Chen R, Hunter Z, Piotrowski-Daspit A, Luker G, Moore BB, Shea L
Biomaterials
· 2026 Jun · PMID 42372506
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Organ fibrosis presents a substantial disease burden with few therapeutic options. Innate immunity mediates fibrinogenesis, but also plays a major role in fibrinolysis. Here, we show that immunomodulatory nanoparticles (...Organ fibrosis presents a substantial disease burden with few therapeutic options. Innate immunity mediates fibrinogenesis, but also plays a major role in fibrinolysis. Here, we show that immunomodulatory nanoparticles (NPs) can harness this endogenous antifibrotic capacity by catalyzing monocyte activation leading to resolution of bleomycin-induced pulmonary fibrosis in vivo. Cargo-free NPs comprised of the degradable biopolymer poly(lactide-co-glycolide) (PLG) induce a transcriptional shift toward antifibrotic immune activation in profibrotic M2 macrophages (MΦs) in vitro. NPs stimulate M2 MΦs toward a glycolytic, rather than fatty acid oxidative, metabolism; suppress canonical M2 markers like arginase-1 (Arg1) and periostin ( ); and upregulate collagenases, hyaluronidases and immunoregulatory factors. When delivered intravenously in vivo, NPs resolve established bleomycin-induced pulmonary fibrosis and invert the trajectory of over 1000 genes from pre- to post-treatment according to bulk RNA-sequencing. NPs also suppress profibrotic signaling and increase expression of repair-associated pathways like peroxisome proliferator-activated receptor gamma (PPAR-γ), nuclear retinoic acid receptor (RAR), vascular endothelial growth factor (VEGF), and sphingolipid signaling in fibrotic lungs. Flow cytometry confirms that NPs induce monocyte recruitment to fibrotic lungs via enhanced integrin expression. Altogether, NPs induce a robust pro-regenerative signature comprised of ECM degradation, inflammation resolution, and tissue repair pathways, concomitant with increased NP+ monocyte recruitment to fibrotic lungs. This work demonstrates that monocytes are not intrinsically profibrotic, but rather, their effects are context-dependent, and they retain a capacity for fibrotic resolution under conditions that can be induced by materials with translational potential.
Wang R, Pan Q, Huang Y
… +3 more, Dai W, Ping Y, Jin Q
Biomaterials
· 2026 Jun · PMID 42372505
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The development of versatile nanoplatforms capable of universally encapsulating diverse bioactive molecules holds significant promise in biomedicine. In this study, size-tunable hollow Ca-tannic acid (TA) nanoparticles (...The development of versatile nanoplatforms capable of universally encapsulating diverse bioactive molecules holds significant promise in biomedicine. In this study, size-tunable hollow Ca-tannic acid (TA) nanoparticles (HCT NPs) are synthesized as universally applicable drug nanocarriers by simply adding TA into amorphous calcium carbonate nanoparticles. The formation of HCT NPs is identified as a surface-protected self-etching process. A wide range of hydrophobic and hydrophilic small-molecule drugs, metal ions, and biomacromolecules including proteins and nucleic acids can be encapsulated in HCT NPs for efficient intracellular delivery. HCT NPs show rapid and efficient endosomal escape, which is crucial for maintaining the bioactivity of biomacromolecules. Remarkably, a wide array of cargo proteins, spanning different molecular weights and isoelectric points can be delivered into the cytosol by HCT NPs without compromising their bioactivities. The therapeutic potential of HCT NPs for intracellular cargo delivery is exemplified by cytosolic delivery of Cas9 plasmids and Cas9 ribonucleoprotein (RNP) for CRISPR-Cas9 genome editing both in vitro and in vivo. The facile and ultrafast synthesis, versatile cargo encapsulation capabilities, efficient cell uptake and endosomal escape, and excellent biocompatibility make HCT NPs a prominent candidate for intracellular delivery of diverse bioactive molecules, particularly in therapeutic applications such as genome editing.
Hu H, Zhao S, Xu L
… +4 more, Ma Z, Ma R, Huang F, Shi L
Biomaterials
· 2026 Jun · PMID 42364498
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Mitochondrial dysfunction is recognized as a key pathogenic mechanism of Alzheimer's disease (AD), involving a self-perpetuating feedback loop with three aspects: upstream β-amyloid protein (Aβ), downstream calcium ion (...Mitochondrial dysfunction is recognized as a key pathogenic mechanism of Alzheimer's disease (AD), involving a self-perpetuating feedback loop with three aspects: upstream β-amyloid protein (Aβ), downstream calcium ion (Ca) and reactive oxygen species (ROS). However, current therapeutic strategies only focus on one aspect and fail to address multiple factors within this cycle. Moreover, the lack of targeted approaches to the mitochondria within damaged neurons further limits their application. Herein, we developed a sequential targeting nanochaperone to selectively target damaged neuronal mitochondria and disrupt this vicious cycle for AD treatment. In this strategy, with the sequence mediation of damaged neuron-targeting and mitochondria-targeting peptides decorated on surface, the nanochaperone can first localize to the damaged neurons in AD brain and then translocate to mitochondria within them. Subsequently, this nanochaperone can effectively bind upstream Aβ proteins and inhibit their aggregation toxicity to mitochondria through the synergic effect of chaperone-mimicking microdomains and Aβ-targeting peptide on surface, thereby halting downstream mitochondrial Ca dyshomeostasis and ROS overload in the damaged neuron. Furthermore, the modified mitochondria-targeting peptide with antioxidant property can further scavenge overproduced ROS and regulate Ca homeostasis, which in turn contributes to reducing the Aβ-induced mitochondrial damage. Consequently, the nanochaperone efficiently restores the mitochondrial dysfunction by disrupting the self-amplifying feedback loop of "Aβ-Ca-ROS" in the AD mitochondrial microenvironment, resulting in the significant alleviation of neuronal damage and cognitive deficits in 5xFAD transgenic mice. Taken together, our work presents a novel therapeutic strategy against mitochondrial dysfunction for AD treatment.
Ge H, Xu L, Zhang Z
… +4 more, Huang H, Zhou L, Li Z, Liu H
Biomaterials
· 2026 Jun · PMID 42364497
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Reactive oxygen species-mediated afterglow (ROSAF) probes offer great potential in cancer theranostics for their high signal-to-background ratios (SBRs) and intrinsic photodynamic activity. However, previous ROSAF probes...Reactive oxygen species-mediated afterglow (ROSAF) probes offer great potential in cancer theranostics for their high signal-to-background ratios (SBRs) and intrinsic photodynamic activity. However, previous ROSAF probes often require nanocarriers for tumor delivery and suffer from leakage-related signal distortion and oxygen-dependent efficacy loss in hypoxic tumor. Herein, we engineered the negative charge transfer in anionic pentamethine cyanine (ACy5) by rationally introducing strongly electron-withdrawing meso-substituents based on SOCT-ISC. The optimized ROSAF, ACy5-NPy, exhibits a 110 nm red shift in absorption/emission compared to classical Cy5 and stably binds serum albumin (SA). Upon complexation with SA, ACy5-NPy transforms into a powerful type-I ROSAF nanoprobe (ACy5-NPy@BSA), showing a 27.7-fold afterglow enhancement over its monomeric form even under hypoxia. Thanks to oxygen independence and innate tumor-targeting, ACy5-NPy@BSA enables 30-min high-contrast afterglow imaging of pancreatic tumors, with a SBR up to 33.3 and precise lesion delineation. This allows precise afterglow surgical navigation and thorough resection, preventing recurrence for 24 days even in multifocal lesions. Moreover, it mediates efficient PDT, significantly suppressing pancreatic tumor growth and metastasis by activating pyroptosis, supported by the reduced serum levels of cancer markers. Systematic modulation of negative charge transfer yields the first protein afterglow nanoprobe, providing a new strategy for afterglow probe design in cancer management.
Fan H, Li X, Song H
… +9 more, Zhang S, Tian Z, Chen Y, Zhou J, Geng S, Liu H, Wang Y, Sun T, Jiang C
Biomaterials
· 2026 Jun · PMID 42364496
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Under the nutrient-deprived tumor microenvironment (TME) and near-universal KRAS mutations, pancreatic ductal adenocarcinoma (PDAC) exhibits voracious addiction to glutamine metabolism. This aberrant metabolism not only...Under the nutrient-deprived tumor microenvironment (TME) and near-universal KRAS mutations, pancreatic ductal adenocarcinoma (PDAC) exhibits voracious addiction to glutamine metabolism. This aberrant metabolism not only sustains the rapid proliferation of malignant cells, but also shapes a tumor-permissive TME characterized by stromal desmoplasia and immunosuppression, culminating in the clinical refractoriness of PDAC. Although multi-target synergistic modulation of glutamine metabolism is recognized as a requisite antitumor strategy, its implementation is still hampered by the uncontrolled in vivo multi-drug biodistribution. Therefore, glutamine metabolism modulation is in urgent need of precision codelivery of multiple drugs. Herein, we propose an upstream-downstream synergistic glutamine metabolism modulation strategy and develop a size switchable metabolic nanomodulators (J&V@T-PPLN NPs) for precision codelivery of metabolic modulators. This nanomodulator achieves in vivo ratio-precise dual-drug codelivery, synergistically blocking the uptake and utilization of glutamine by PDAC cells. Beyond cutting off nutrient supply to malignant cells, the nanomodulator also demonstrates the capacity to remodel the TME and reactivate antitumor immunity, thereby eliciting enhanced tumor suppression. Through the ratio-precise codelivery system, this study discussed the possibility of translating in vitro validated synergistic metabolism modulation into a controllable in vivo combination therapy modality, providing a generalizable strategy for metabolism modulating cancer therapy and the rational design of precision drug delivery systems.