A Double Network Composite Hydrogel with Self-Regulating Cu2+/Luteolin Release and Mechanical Modulation for Enhanced Wound Healing.

Designing adaptive and smart hydrogel wound dressings to meet specific needs across different stages of wound healing is crucial. Here, we present a composite hydrogel, GSC/PBE@Lut, that offers self-regulating release of cupric ions and luteolin and modulates mechanical properties to promote chronic wound healing. The double network hydrogel, GSC, is fabricated through photo-cross-linking of gelatin methacrylate, followed by Cu2+-alginate coordination cross-linking. On one hand, GSC allows for rapid Cu2+ release to eliminate bacteria in the acidic pH environment during inflammation and reduces the hydrogel's mechanical strength to minimize tissue trauma during early dressing changes. On the other hand, GSC enables slow Cu2+ release during the proliferation stage, promoting angiogenesis and biocompatibility. Furthermore, the inclusion of pH- and reactive oxygen species (ROS)-responsive luteolin nanoparticles (PBE@Lut) in the hydrogel matrix allows for controlled release of luteolin, offering antioxidant and anti-inflammatory effects and promoting anti-inflammatory macrophage polarization. In a murine model of Staphylococcus aureus infected wounds, GSC/PBE@Lut demonstrates exceptional therapeutic benefits in antibacterial, anti-inflammatory, angiogenic, and tissue regeneration. Overall, our results suggest that smart hydrogels with controlled bioactive agent release and mechanical modulation present a promising solution for treating chronic wounds.

Triune Nanomodulator Enables Exhausted Cytotoxic T Lymphocyte Rejuvenation for Cancer Epigenetic Immunotherapy.

Oncogene activation and epigenome dysregulation drive tumor initiation and progression, contributing to tumor immune evasion and compromising the clinical response to immunotherapy. Epigenetic immunotherapy represents a promising paradigm in conquering cancer immunosuppression, whereas few relevant drug combination and delivery strategies emerge in the clinic. This study presents a well-designed triune nanomodulator, termed ROCA, which demonstrates robust capabilities in tumor epigenetic modulation and immune microenvironment reprogramming for cancer epigenetic immunotherapy. The nanomodulator is engineered from a nanoscale framework with epigenetic modulation and cascaded catalytic activity, which self-assembles into a nanoaggregate with tumor targeting polypeptide decoration that enables loading of the immunogenic cell death (ICD)-inducing agent. The nanomodulator releases active factors specifically triggered in the tumor microenvironment, represses oncogene expression, and initiates the type 1 T helper (TH1) cell chemokine axis by reversing DNA hypermethylation. This process, together with ICD induction, fundamentally reprograms the tumor microenvironment and significantly enhances the rejuvenation of exhausted cytotoxic T lymphocytes (CTLs, CD8+ T cells), which synergizes with the anti-PD-L1 immune checkpoint blockade and results in a boosted antitumor immune response. Furthermore, this strategy establishes long-term immune memory and effectively prevents orthotopic colon cancer relapse. Therefore, the nanomodulator holds promise as a standalone epigenetic immunotherapy agent or as part of a combination therapy with immune checkpoint inhibitors in preclinical cancer models, broadening the array of combinatorial strategies in cancer immunotherapy.

A lipid/PLGA nanocomplex to reshape tumor immune microenvironment for colon cancer therapy.

Immune checkpoint blockade therapy provides a new strategy for tumor treatment; however, the insufficient infiltration of cytotoxic T cells and immunosuppression in tumor microenvironment lead to unsatisfied effects. Herein, we reported a lipid/PLGA nanocomplex (RDCM) co-loaded with the photosensitizer Ce6 and the indoleamine 2,3-dioxygenase (IDO) inhibitor 1MT to improve immunotherapy of colon cancer. Arginine-glycine-aspartic acid (RGD) as the targeting moiety was conjugated on 1,2-distearoyl-snglycero-3-phosphoethanolamine lipid via polyethylene glycol (PEG), and programmed cell death-ligand 1 (PD-L1) peptide inhibitor DPPA (sequence: CPLGVRGK-GGG-d(NYSKPTDRQYHF)) was immobilized on the terminal group of PEG via matrix metalloproteinase 2 sensitive peptide linker. The Ce6 and 1MT were encapsulated in PLGA nanoparticles. The drug loaded nanoparticles were composited with RGD and DPPA modified lipid and lecithin to form lipid/PLGA nanocomplexes. When the nanocomplexes were delivered to tumor, DPPA was released by the cleavage of a matrix metalloproteinase 2-sensitive peptide linker for PD-L1 binding. RGD facilitated the cellular internalization of nanocomplexes via avß3 integrin. Strong immunogenic cell death was induced by 1O2 generated from Ce6 irradiation under 660 nm laser. 1MT inhibited the activity of IDO and reduced the inhibition of cytotoxic T cells caused by kynurenine accumulation in the tumor microenvironment. The RDCM facilitated the maturation of dendritic cells, inhibited the activity of IDO, and markedly recruited the proportion of tumor-infiltrating cytotoxic T cells in CT26 tumor-bearing mice, triggering a robust immunological memory effect, thus effectively preventing tumor metastasis. The results indicated that the RDCM with dual IDO and PD-L1 inhibition effects is a promising platform for targeted photoimmunotherapy of colon cancer.

A Biodegradable Janus Sponge for Negative Pressure Wound Therapy.

Negative pressure wound therapy (NPWT) is effective in repairing serious skin injury. The dressing used in the NPWT is important for wound healing. In this paper, we develop biodegradable amphiphilic polyurethanes (PUs) and fabricate the PUs into sponges as wound dressings (Bi@e) with Janus pore architectures for NPWT. The Bi@e is adaptive to all the stages of the wound healing process. The Janus Bi@e sponge consists of two layers: the dense hydrophobic upper layer with small pores provides protection and support during negative pressure drainage, and the loose hydrophilic lower layer with large pores absorbs large amounts of wound exudate and maintains a moist environment. Additionally, antibacterial agent silver sulfadiazine (SSD) is loaded into the sponge against Escherichia coli and Staphylococcus aureus with a concentration of 0.50 wt%. The Janus sponge exhibits a super absorbent capacity of 19.53 times its own water weight and remarkable resistance to compression. In a rat skin defect model, the Janus Bi@e sponge not only prevents the conglutination between regenerative skin and dressing but also accelerates wound healing compared to commercially available NPWT dressing. The Janus Bi@e sponge is a promising dressing for the NPWT.

Oxidase-like manganese oxide nanoparticles: a mechanism of organic acids/aldehydes as electron acceptors and potential application in cancer therapy.

Identifying the underlying catalytic mechanisms of synthetic nanocatalysts or nanozymes is important in directing their design and applications. Herein, we revisited the oxidation process of 4,4'-diamino-3,3',5,5'-tetramethylbiphenyl (TMB) by Mn3O4 nanoparticles and revealed that it adopted an organic acid/aldehyde-triggered catalytic mechanism at a weakly acidic or neutral pH, which is O2-independent and inhibited by the pre-addition of H2O2. Importantly, similar organic acid/aldehyde-mediated oxidation was applied to other substrates of peroxidase in the presence of nanoparticulate or commercially available MnO2 and Mn2O3 but not MnO. The selective oxidation of TMB by Mn3O4 over MnO was further supported by density functional theory calculations. Moreover, Mn3O4 nanoparticles enabled the oxidation of indole 3-acetic acid, a substrate that can generate cytotoxic singlet oxygen upon single-electron transfer oxidation, displaying potential in nanocatalytic tumor therapy. Overall, we revealed a general catalytic mechanism of manganese oxides towards the oxidation of peroxidase substrates, which could boost the design and various applications of these manganese-based nanoparticles.

A mitochondria-targeted anticancer copper dithiocarbamate amplifies immunogenic cuproptosis and macrophage polarization.

The way that cancer cells die inspires treatment regimens and cytolytic cuproptosis induced by copper complexes, like copper(II) bis(diethyldithiocarbamate) (CuET), has emerged as a novel therapeutic target. Herein, a triphenylphosphonium-modified CuET (TPP-CuET) is designed to target mitochondrial metabolism, triggering intense immunogenic cuproptosis in breast cancer cells and remodeling tumor-associated macrophages. TPP-CuET enables an enhanced mitochondrial copper accumulation in comparison to CuET (29.0% vs. 19.4%), and severely disrupts the morphology and functions of mitochondria, encompassing the tricarboxylic acid cycle, ATP synthesis, and electron transfer chain. Importantly, it triggers amplified immunogenic death of cancer cells, and the released damage-associated molecular patterns effectively induce M1 polarization and migration of macrophages. Transcriptome analysis further reveals that TPP-CuET promotes antigen processing and presentation in cancer cells through the MHC I pathway, activating the immune response of CD8 T cells and natural killer cells. To the best of our knowledge, TPP-CuET is the first mitochondrial targeted immunogenic cuproptosis inducer and is expected to flourish in antitumor immunotherapy.

An Engineered Butyrate-Derived Polymer Nanoplatform as a Mucosa-Healing Enhancer Potentiates the Therapeutic Effect of Magnolol in Inflammatory Bowel Disease.

Colonic epithelial damage and dysregulated immune response are crucial factors in the progression and exacerbation of inflammatory bowel disease (IBD). Nanoenabled targeted drug delivery to the inflamed intestinal mucosa has shown promise in inducing and maintaining colitis remission, while minimizing side effects. Inspired by the excellent antioxidative and anti-inflammatory efficacy of naturally derived magnolol (Mag) and gut homeostasis regulation of microbiota-derived butyrate, we developed a pH/redox dual-responsive butyrate-rich polymer nanoparticle (PSBA) as an oral Mag delivery system for combinational therapy of IBD. PSBA showed a high butyrate content of 22% and effectively encapsulated Mag. The Mag-loaded nanoparticles (PSBA@Mag) demonstrated colonic pH and reduction-responsive drug release, ensuring efficient retention and adhesion in the colon of colitis mice. PSBA@Mag not only normalized the level of reactive oxygen species and inflammatory effectors in inflamed colonic mucosa but also restored the epithelial barrier function in both ulcerative colitis and Crohn's disease mouse models. Importantly, PSBA promoted the migration and healing ability of intestinal epithelial cells in vitro and in vivo, sensitizing the therapeutic efficacy of Mag in animal models. Moreover, transcriptomics and metabolism analyses revealed that PSBA@Mag mitigated inflammation by suppressing the production of pro-inflammatory cytokines and chemokines and restoring the lipid metabolism. Additionally, this nanomedicine modulated the gut microbiota by inhibiting pathogenic Proteus and Escherichia-Shigella and promoting the proliferation of beneficial probiotics, including Lachnoclostridium, Lachnospiraceae_NK4A136_group and norank_f_Ruminococcaceae. Overall, our findings highlight the potential of butyrate-functionalized polymethacrylates as versatile and effective nanoplatforms for colonic drug delivery and mucosa repair in combating IBD and other gastrointestinal disorders.

Nano-enabled colorectal cancer therapy.

Colorectal cancer (CRC), one of the most common and deadliest diseases worldwide, poses a great health threat and social burden. The clinical treatments of CRC encompassing surgery, chemotherapy, and radiotherapy are challenged with toxicity, therapy resistance, and recurrence. In the past two decades, targeted therapy and immunotherapy have greatly improved the therapeutic benefits of CRC patients but they still suffer from drug resistance and low response rates. Very recently, gut microbiota regulation has exhibited a great potential in preventing and treating CRC, as well as in modulating the efficacy and toxicity of chemotherapy and immunotherapy. In this review, we provide a cutting-edge summary of nanomedicine-based treatment in colorectal cancer, highlighting the recent progress of oral and systemic tumor-targeting and/or tumor-activatable drug delivery systems as well as novel therapeutic strategies against CRC, including nano-sensitizing immunotherapy, anti-inflammation, gut microbiota modulation therapy, etc. Finally, the recent endeavors to address therapy resistance, metastasis, and recurrence in CRC were discussed. We hope this review could offer insight into the design and development of nanomedicines for CRC and beyond.

Orally Administrated Olsalazine-Loaded Multilayer Pectin/Chitosan/Alginate Composite Microspheres for Ulcerative Colitis Treatment.

The pathogenesis of inflammatory bowel diseases (IBDs) including ulcerative colitis (UC) and Crohn's disease is extremely cloudy. Maintaining the level of remission lesions in colitis is the default treatment attitude at present. Epithelial barrier restoration is considered as the same important strategy as colonic targeted drug delivery in UC treatment. In this paper, we developed a multilayer natural polysaccharide microsphere (pectin/chitosan/alginate) with pH and enzyme dual sensitivity to reduce the loss of medication in the upper digestive tract and preferentially adhere to exposed epithelial cells in colonic tissues by electrostatic forces for efficiently targeted UC treatment. Olsalazine as an inflammatory drug was efficiently loaded in the chitosan layer and realized a colonic pH-responsive drug release. Furthermore, the multilayer microspheres exhibited excellent capability in suppressing harmful flora and a bio-adhesion effect to extend the duration of local medicine. In the in vivo anti-colitis study, the downregulated levels of pro-inflammatory factors and the increase of tight junction protein indicated the excellent anti-inflammation effect of the olsalazine-loaded microspheres. In summary, these results showed that the multilayer natural polysaccharide microspheres could be a powerful candidate in the targeted drug delivery system for UC therapy.

Bio-adhesive and ROS-scavenging hydrogel microspheres for targeted ulcerative colitis therapy.

Ulcerative colitis (UC) as an important type of inflammatory bowel disease is a chronic disease characterized by intestinal dyshomeostasis. The UC treatment is challenged by the insufficiency of drug delivery and retention. Herein, we fabricated an intrarectal formulation of olsalazine (Olsa)-loaded hydrogel microspheres (LDKT/Olsa) with good bio-adhesiveness and reactive oxygen species (ROS)-scavenging ability to enhance drug retention and therapeutic effect. Low methoxy pectin-dopamine conjugate/konjac glucomannan composite hydrogel microspheres (LDKT) with a size ranging from 10 to 100 µm were prepared by using Zn2+ and ROS-sensitive thioketal as crosslinkers. Upon intrarectal administration, the negatively charged and dopamine-functionalized hydrogel microspheres efficiently adhered to cationic surface of inflammatory mucosa, scavenging ROS and releasing Zn2+ and Olsa for antibacterial and anti-inflammatory effects. In the dextran sodium sulfate (DSS)-induced mouse UC model, the microspheres significantly reduced the levels of colonic ROS and pro-inflammatory cytokines, improved gut mucosal barrier integrity, and remarkably relieved colitis. Overall, the LDKT microspheres are promising carriers to deliver drugs for UC treatment.

Reactive oxygen species-upregulating nanomedicines towards enhanced cancer therapy.

Reactive oxygen species (ROS) play a crucial role in physiological and pathological processes, emerging as a therapeutic target in cancer. Owing to the high concentration of ROS in solid tumor tissues, ROS-based treatments, such as photodynamic therapy and chemodynamic therapy, and ROS-responsive drug delivery systems have been widely explored to powerfully and specifically suppress tumors. However, their anticancer efficacy is still hampered by the heterogeneous ROS levels, and thus comprehensively upregulating the ROS levels in tumor tissues can ensure an enhanced therapeutic effect, which can further sensitize and/or synergize with other therapies to inhibit tumor growth and metastasis. Herein, we review the recently emerging drug delivery strategies and technologies for increasing the H2O2, ˙OH, 1O2, and ˙O2- concentrations in cancer cells, including the efficient delivery of natural enzymes, nanozymes, small molecular biological molecules, and nanoscale Fenton-reagents and semiconductors and neutralization of intracellular antioxidant substances and localized input of mechanical and electromagnetic waves (such as ultrasound, near infrared light, microwaves, and X-rays). The applications of these ROS-upregulating nanosystems in enhancing and synergizing cancer therapies including chemotherapy, chemodynamic therapy, phototherapy, and immunotherapy are surveyed. In addition, we discuss the challenges of ROS-upregulating systems and the prospects for future studies.

Recent Advances in Boosting EGFR Tyrosine Kinase Inhibitors-Based Cancer Therapy.

Epidermal growth factor receptor (EGFR) plays a key role in signal transduction pathways associated with cell proliferation, growth, and survival. Its overexpression and aberrant activation in malignancy correlate with poor prognosis and short survival. Targeting inhibition of EGFR by small-molecular tyrosine kinase inhibitors (TKIs) is emerging as an important treatment model besides of chemotherapy, greatly reshaping the landscape of cancer therapy. However, they are still challenged by the off-targeted toxicity, relatively limited cancer types, and drug resistance after long-term therapy. In this review, we summarize the recent progress of oral, pulmonary, and injectable drug delivery systems for enhanced and targeting TKI delivery to tumors and reduced side effects. Importantly, EGFR-TKI-based combination therapies not only greatly broaden the applicable cancer types of EGFR-TKI but also significantly improve the anticancer effect. The mechanisms of TKI resistance are summarized, and current strategies to overcome TKI resistance as well as the application of TKI in reversing chemotherapy resistance are discussed. Finally, we provide a perspective on the future research of EGFR-TKI-based cancer therapy.

Harnessing polymer-derived drug delivery systems for combating inflammatory bowel disease.

The inflammatory bowel disease (IBD) is incurable, chronic, recrudescent disorders in the inflamed intestines. Current clinic treatments are challenged by systemic exposure-induced severe side effects, inefficiency after long-term treatment, and increased risks of infection and malignancy due to immunosuppression. Fortunately, naturally bioactive small molecules, reactive oxygen species scavengers (or antioxidants), and gut microbiota modulators have emerged as promising candidates for the IBD treatment. Polymeric systems have been engineered as a delivery vehicle to improve the bioavailability and efficacy of these therapeutic agents through targeting the mucosa and enhancing intestinal adhesion and retention, and reduce their systemic toxicity. Herein we survey polymer-derived drug delivery systems for combating the IBD. Advanced delivery technologies, therapeutic intervention strategies, and the principles for the construction of hierarchical, mucosa-targeting, and bioresponsive systems are elaborated, providing insights into design and development of from-bench-to-bedside drug delivery polymeric systems for the IBD treatment.

Copper-olsalazine metal-organic frameworks as a nanocatalyst and epigenetic modulator for efficient inhibition of colorectal cancer growth and metastasis.

Despite the extensive explorations of nanoscale metal-organic frameworks (nanoMOFs) in drug delivery, the intrinsic bioactivity of nanoMOFs, such as anticancer activity, is severely underestimated owing to the overlooked integration of the hierarchical components including nanosized MOFs and molecular-level organic ligands and metal-organic complexes. Herein, we propose a de novo design of multifunctional bioactive nanoMOFs ranging from molecular to nanoscale level, and demonstrate this proof-of-concept by a copper-olsalazine (Olsa, a clinically approved drug for inflammatory bowel disease, here as a bioactive linker and DNA hypomethylating agent) nanoMOF displaying a multifaceted anticancer mechanism: (1) Cu-Olsa nanoMOF-mediated redox dyshomeostasis for enhanced catalytic tumor therapy, (2) targeting downregulation of cyclooxygenase-2 by the organic complex of Cu2+ and Olsa, and (3) Olsa-mediated epigenetic regulation. Cu-Olsa nanoMOF displayed an enzyme-like catalytic activity to generate cancericidal species ·OH and 1O2 from rich H2O2 in tumors, improved the expression of tumor suppressors TIMP3 and AXIN2 by epigenetic modulation, and fulfilled selective inhibition of colorectal cancer cells over normal cells. The hyaluronic acid-modified nanoMOF further verified the efficient suppression of CT26 colorectal tumor growth and metastasis in murine models. Overall, these results suggest that Olsa-based MOF presents a platform of epigenetic therapy-synergized nanomedicine for efficient cancer treatment and provides a powerful strategy for the design of intrinsically bioactive nanoMOFs. STATEMENT OF SIGNIFICANCE: Metal-organic frameworks (MOFs) with intrinsic bioactivities such as anticancer and antibacterial activity are of great interest. Herein, we reported a bioactive copper-olsalazine (Cu-Olsa) nanoMOF as a nanodrug for colorectal cancer treatment. This nanoMOF per se displayed enzyme-like catalytic activity to generate cancericidal species ·OH and 1O2 from rich H2O2 in tumors for nanocatalytic tumor therapy. Upon dissociation into small molecular copper-organic complex and olsalazine in cancer cells, COX-2 inhibition and epigenetic modulation were fulfilled for selective inhibition of colorectal cancer growth and metastasis.

Co-Delivery of Doxorubicin and Anti-PD-L1 Peptide in Lipid/PLGA Nanocomplexes for the Chemo-Immunotherapy of Cancer.

The combined delivery of chemotherapeutics with checkpoint inhibitors of the PD-1/PD-L1 pathway provides a new approach for cancer treatment. Small-molecule peptide inhibitors possess short production cycle, low immunogenicity, and fewer side effects; however, their potential in cancer therapy is hampered by the rapid biodegradation and a nanocarrier is needed for efficient drug delivery. Herein, anticancer drug doxorubicin (DOX) and PD-L1 inhibitor peptide P-12 are co-loaded by a lipid polymer nanocomplex based on poly(lactic-co-glycolic acid) (PLGA) and DSPE-PEG. Octaarginine (R8)-conjugated DSPE-PEG renders the LPN efficient internalization by cancer cells. The optimal nanomedicine LPN-30-R82K@DP shows a diameter of 125 nm and a DOX and P-12 loading content of 5.0 and 6.2%, respectively. LPN-30-R82K@DP exhibits good physiological stability and enhanced cellular uptake by cancer cells. It successfully induces immunogenic cell death and PD-L1 blockade in CT26 cancer cells. The in vivo antitumor study further suggests that co-loaded nanomedicine efficiently suppresses CT26 tumor growth and elicits antitumor immune response. This study manifests that lipid polymer nanocomplexes are promising drug carriers for the efficient chemo-immunotherapy of cancer.

A reactive oxygen species-replenishing coordination polymer nanomedicine disrupts redox homeostasis and induces concurrent apoptosis-ferroptosis for combinational cancer therapy.

Reactive oxygen species (ROS) are important signal molecules and imbalanced ROS level could lead to cell death. Elevated ROS levels in tumor tissues offer an opportunity to design ROS-responsive drug delivery systems (DDSs) or ROS-based cancer therapies such as chemodynamic therapy. However, their anticancer efficacies are hampered by the ROS-consuming nature of these DDSs as well as the high concentration of reductive agents like glutathione (GSH). Here we developed a doxorubicin (DOX)-incorporated iron coordination polymer nanoparticle (PCFD) for efficient chemo-chemodynamic cancer therapy by using a cinnamaldehyde (CA)-based ROS-replenishing organic ligand (TCA). TCA can ROS-responsively release CA to supplement intracellular ROS and deplete GSH by a thiol-Michael addition reaction, which together with DOX-triggered ROS upregulation and Fe3+-enabled GSH depletion facilitated efficient DOX release and enhanced Fenton reaction, thereby inducing redox dyshomeostasis and cancer cell death in a concurrent apoptosis-ferroptosis way. Both in vitro and in vivo studies revealed that ROS-replenishing PCFD exhibited much better anticancer effect than ROS-consuming control nanoparticle PAFD. The ingenious ROS-replenishing strategy could be expanded to construct versatile ROS-responsive DDSs and ROS-based nanomedicines with potentiated anticancer activity. STATEMENT OF SIGNIFICANCE: We develop a doxorubicin (DOX)-incorporated iron coordination polymer nanoparticle (PCFD) for efficient chemo-chemodynamic cancer therapy by using a cinnamaldehyde-based reactive oxygen species (ROS)-replenishing organic ligand. This functional ligand can ROS-responsively release cinnamaldehyde to supplement intracellular H2O2 and deplete glutathione (GSH) by a thiol-Michael addition reaction, which together with DOX-triggered ROS upregulation and Fe3+-enabled GSH depletion facilitates efficient DOX release and enhanced Fenton reaction, thereby inducing redox dyshomeostasis and cancer cell death in a concurrent apoptosis-ferroptosis way. Both in vitro and in vivo studies reveal that ROS-replenishing PCFD exhibit much better anticancer effect than ROS consuming counterpart. This study provides a facile and straightforward strategy to design ROS amplifying nanoplatforms for cancer treatment.

Photo-enhanced upcycling H2O2 into hydroxyl radicals by IR780-embedded Fe3O4@MIL-100 for intense nanocatalytic tumor therapy.

Reactive oxygen species (ROS)-based nanocatalytic tumor therapy is alluring owing to the capability to generate highly cytotoxic ∙OH radicals from tumoral H2O2. However, the antitumor efficacy is highly dependent on the radical generation efficiency and challenged by the high levels of antioxidative glutathione (GSH) in cancer cells. Herein, we report an IR-780 decorated, GSH-depleting Fe3O4@MIL-100 (IFM) nanocomposite for photo-enhanced tumor catalytic therapy by extensive production of ∙OH, which is realized by an integration of excellent peroxidase-like activity of IFM, selective upregulation of tumoral H2O2 by ß-lapachone, and localized hyperthermia by near infrared light irradiation. IFM shows potentiated antiproliferative effect in 4T1 cancer cells by ∙OH overproduction and glutathione scavenging, inducing intracellular redox dyshomeostasis and cell death by concurrent apoptosis and ferroptosis. In vivo antitumor investigation further demonstrates photoacoustic and fluorescence imaging-guided combinational therapy with a tumor inhibition rate of 96.4%. This study provides a strategy of photo-enhanced nanocatalytic tumor therapy by tumor-specific H2O2 amplification and hyperthermia.

Reversal of cisplatin chemotherapy resistance by glutathione-resistant copper-based nanomedicine via cuproptosis.

Platinum-based chemotherapy is widely used to treat various cancers. However, exogenous platinum is likely to cause severe side effects and drug resistance induced by upregulated glutathione (GSH) in cancer cells poses a threat to the management of cancer progression and recurrence. Anticancer copper-organic complexes are excellent candidates to substitute platinum-based chemotherapeutics, exhibiting lower systemic toxicity and even overcoming platinum-based chemotherapy resistance. Here, we report the GSH-resistance of copper(II) bis(diethyldithiocarbamate) (CuET) and its reversal of cisplatin resistance in non-small-cell lung cancer via cuproptosis. Electrochemistry and UV-vis spectroscopy studies demonstrate that CuET possesses a lower reduction potential and the reaction inertness with GSH. Importantly, CuET overcomes the drug resistance of A549/DDP cells and the anticancer effect is hardly affected by intracellular GSH levels. To improve the solubility and bioavailability, bovine serum albumin-stabilized CuET nanoparticles (NPs) are prepared and they have a high drug loading content of 27.5% and excellent physiological stability. In vitro studies manifest that CuET NPs augment the distributions in the cytosol and cytoskeleton, inducing cell death via cuproptosis in A549/DDP cells, which is distinctly different from the apoptosis pattern induced by cisplatin. In vivo antitumor evaluation shows that the nanomedicine has superior biosafety and potent antitumor activity in a cisplatin-resistant tumor model. Our study suggests that copper-organic complex-based nanosystems could be a powerful toolbox to tackle the platinum-based drug resistance and systemic toxicity concerns.

Multifunctional thermo-sensitive hydrogel for modulating the microenvironment in Osteoarthritis by polarizing macrophages and scavenging RONS.

Osteoarthritis (OA) is a common degenerative joint disease that can lead to disability. Blocking the complex malignant feedback loop system dominated by oxidative stress and pro-inflammatory factors is the key to treating OA. Here, we develop a multifunctional composite thermo-sensitive hydrogel (HPP@Cu gel), which is utilized by Poloxamer 407 (P407) and hyaluronic acid (HA) mixture as the gel matrix, then physically mixed with copper nanodots (Cu NDs) and platelet-rich plasma (PRP). Cu NDs is a novel nano-scavenger of reactive oxygen and nitrogen species (RONS) with efficient free radical scavenging activity. HPP@Cu gel is injected into the articular cavity, where it form an in situ gel that slowly released Cu NDs, HA, and PRP, prolonging the duration of drug action. Our results indicate that HPP@Cu gel could efficiently remove RONS from inflammatory sites and promote repolarization of macrophages to an anti-inflammatory phenotype. The HPP@Cu gel therapy dramatically reduces cartilage degradation and inflammatory factor production in OA rats. This study provides a reliable reference for the application of injectable hydrogels in inflammatory diseases associated with oxidative stress.

Copper-based metal-organic frameworks for biomedical applications.

Metal-organic frameworks (MOFs) are a class of important porous, crystalline materials composed of metal ions (clusters) and organic ligands. Owing to the unique redox chemistry, photochemical and electrical property, and catalytic activity of Cu2+/+, copper-based MOFs (Cu-MOFs) have been recently and extensively explored in various biomedical fields. In this review, we first make a brief introduction to the synthesis of Cu-MOFs and their composites, and highlight the recent synthetic strategies of two most studied representatives, three-dimensional HKUST-1 and two-dimensional Cu-TCPP. The recent advances of Cu-MOFs in the applications of cancer treatment, bacterial inhibition, biosensing, biocatalysis, and wound healing are summarized and discussed. Furthermore, we propose a prospect of the future development of Cu-MOFs in biomedical fields and beyond.