Injectable Zwitterionic Physical Hydrogel with Enhanced Chemodynamic Therapy and Tumor Microenvironment Remodeling Properties for Synergistic Anticancer Therapy.
ACS nano
Surgical resection is the first-line therapy for breast cancer. However, residual tumor cells and the highly immunosuppressive tumor microenvironment (TME) continue to have a serious impact on tumor recurrence and metastasis postresection. Implantation of an hydrogel system postresection has shown to be an effective treatment with great clinical potential. Herein, an injectable zwitterionic hydrogel system was developed for local drug delivery with enhanced immune activation and prevention of tumor recurrence. Driven by electrostatic interactions, poly(sulfobetaine methacrylate) (PSBMA) self-assembles into a hydrogel in saline, achieving low protein adsorption and tunable biodegradability. The chemotherapy drug doxorubicin (DOX) was loaded into copper peroxide nanoparticles (CuO/DOX), which were coated with macrophage membranes to form tumor-targeting nanoparticles (M/CuO/DOX). Next, M/CuO/DOX and the stimulator of interferon genes (STING) agonist 2',3'-cGAMP were coloaded into PSBMA hydrogel (Gel@M/CuO/DOX/STING). The hydrophilic STING agonist was first released by diffusion from hydrogel to activate the STING pathway and upregulate interferon (IFN) signaling related genes, remodeling the immunosuppressive TME. Then, M/CuO/DOX targeted the residual tumor cells, combining with DOX-induced DNA damage, immunogenic tumor cell death, and copper death. Hence, this work combines chemodynamic therapy with STING pathway activation in TME, encouraging residual tumor cell death, promoting the maturation of dendritic cells, enhancing tumor-specific CD8 T cell infiltration, and preventing postoperative recurrence and metastasis.
10.1021/acsnano.3c05898
A Polymeric Hydrogel to Eliminate Programmed Death-Ligand 1 for Enhanced Tumor Radio-Immunotherapy.
ACS nano
Programmed death-ligand 1 (PD-L1) is a specialized shield on tumor cells that evades the immune system. Even inhibited by PD-L1 antibodies, a cycling process constantly transports PD-L1 from inside to outside of cells, facilitating the renewal and replenishment of PD-L1 on the cancer cell membrane. Herein, we develop a sodium alginate hydrogel consisting of elesclomol-Cu and galactose to induce persistent cuproptosis, leading to the reduction of PD-L1 for radio-immunotherapy of colon tumors. First, a prefabricated hydrogel is synthesized by immobilizing elesclomol onto a sodium alginate saccharide chain through the coordination with bivalent copper ions (Cu), followed by incorporation of galactose. After implantation into the tumors, this prefabricated hydrogel can be further cross-linked in the presence of physiological calcium ions (Ca), resulting in the formation of a hydrogel with controlled release of elesclomol-Cu (ES-Cu) and galactose. The hydrogel effectively induces the oligomerization of DLAT and cuproptosis in colorectal cancer cells. Interestingly, radiation-induced PD-L1 upregulation is abrogated in the presence of the hydrogel, releasing ES-Cu and galactose. Consequently, the sensitization of tumor to radiotherapy and immunotherapy is significantly improved, further prolonging the survival of tumor-bearing mice in both local and metastatic tumors. Our study introduces an approach that combines cuproptosis with immunotherapy and radiotherapy.
10.1021/acsnano.3c08875
Photothermally Triggered Copper Payload Release for Cuproptosis-Promoted Cancer Synergistic Therapy.
Angewandte Chemie (International ed. in English)
Cuproptosis is a new form of programmed cell death and exhibits enormous potential in cancer treatment. However, reducing the undesirable Cu ion release in normal tissue and maximizing the copper-induced therapeutic effect in cancer sites are two main challenges. In this study, we constructed a photothermally triggered nanoplatform (Au@MSN-Cu/PEG/DSF) to realize on-demand delivery for synergistic therapy. The released disulfiram (DSF) chelated with Cu in situ to generate highly cytotoxic bis(diethyldithiocarbamate)copper (CuET), causing cell apoptosis, and the formed Cu species promoted toxic mitochondrial protein aggregation, leading to cell cuproptosis. Synergistic with photothermal therapy, Au@MSN-Cu/PEG/DSF could effectively kill tumor cells and inhibit tumor growth (inhibition rate up to 80.1 %). These results provide a promising perspective for potential cancer treatment based on cuproptosis, and may also inspire the design of advanced nano-therapeutic platforms.
10.1002/anie.202213922
Cuproptosis Induced by ROS Responsive Nanoparticles with Elesclomol and Copper Combined with αPD-L1 for Enhanced Cancer Immunotherapy.
Advanced materials (Deerfield Beach, Fla.)
Cuproptosis is a new cell death that depends on copper (Cu) ionophores to transport Cu into cancer cells, which induces cell death. However, existing Cu ionophores are small molecules with a short blood half-life making it hard to transport enough Cu into cancer cells. Herein, a reactive oxygen species (ROS)-sensitive polymer (PHPM) is designed, which is used to co-encapsulate elesclomol (ES) and Cu to form nanoparticles (NP@ESCu). After entering cancer cells, ES and Cu, triggered by excessive intracellular ROS, are readily released. ES and Cu work in a concerted way to not only kill cancer cells by cuproptosis, but also induce immune responses. In vitro, the ability of NP@ESCu to efficiently transport Cu and induce cuproptosis is investigated. In addition, the change in the transcriptomes of cancer cells treated with NP@ESCu is explored by RNA-Seq. In vivo, NP@ESCu is found to induce cuproptosis in the mice model with subcutaneous bladder cancer, reprograming the tumor microenvironment. Additionally, NP@ESCu is further combined with anti-programmed cell death protein ligand-1 antibody (αPD-L1). This study provides the first report of combining nanomedicine that can induce cuproptosis with αPD-L1 for enhanced cancer therapy, thereby providing a novel strategy for future cancer therapy.
10.1002/adma.202212267
Black Titania Janus Mesoporous Nanomotor for Enhanced Tumor Penetration and Near-Infrared Light-Triggered Photodynamic Therapy.
ACS nano
Thanks to their excellent photoelectric characteristics to generate cytotoxic reactive oxygen species (ROS) under the light-activation process, TiO nanomaterials have shown significant potential in photodynamic therapy (PDT) for solid tumors. Nevertheless, the limited penetration depth of TiO-based photosensitizers and excitation sources (UV/visible light) for PDT remains a formidable challenge when confronted with complex tumor microenvironments (TMEs). Here, we present a HO-driven black TiO mesoporous nanomotor with near-infrared (NIR) light absorption capability and autonomous navigation ability, which effectively enhances solid tumor penetration in NIR light-triggered PDT. The nanomotor was rationally designed and fabricated based on the Janus mesoporous nanostructure, which consists of a NIR light-responsive black TiO nanosphere and an enzyme-modified periodic mesoporous organosilica (PMO) nanorod that wraps around the TiO nanosphere. The overexpressed HO can drive the nanomotor in the TME under catalysis of catalase in the PMO domain. By precisely controlling the ratio of TiO and PMO compartments in the Janus nanostructure, TiO&PMO nanomotors can achieve optimal self-propulsive directionality and velocity, enhancing cellular uptake and facilitating deep tumor penetration. Additionally, by the decomposition of endogenous HO within solid tumors, these nanomotors can continuously supply oxygen to enable highly efficient ROS production under the NIR photocatalysis of black TiO, leading to intensified PDT effects and effective tumor inhibition.
10.1021/acsnano.4c03652
Composite Hydrogel for Spatiotemporal Lipid Intervention of Tumor Milieu.
Advanced materials (Deerfield Beach, Fla.)
Induction of immunogenic cell death (ICD) plays crucial roles in cancer immunotherapy, whereas its efficacy is severely compromised by redundant antioxidant defenses in cancer cells and aberrant lipid metabolism in immunosuppressive cell populations. In this work, it is found that hollow mesoporous CuS nanoparticles (NPs) possess an intrinsic capacity of inhibiting glutathione peroxidase 4 (GPX4). When loaded with an inhibitor of the ferroptosis suppressor protein 1 (FSP1), these NPs block two parallel redox systems and cooperate with near-infrared irradiation to reinforce ICD. A hydrogel co-delivering cancer-cell-targeting CuS NPs and immunosuppressive-cell-targeting sulfo-N-succinimidyl oleate (SSO) for spatiotemporal lipid intervention i further fabricated. While the CuS NPs augment ICD via synergistic lipid peroxidation, SSO reinstates immune perception via lipid metabolic reprogramming, thereby coordinately triggering robust innate and adaptive immunity to restrain tumor growth, relapse, and metastasis. This study provides an immunometabolic therapy via orchestrated lipid modulation in the tumor milieu.
10.1002/adma.202211579
Necroptosis-Mediated Synergistic Photodynamic and Glutamine-Metabolic Therapy Enabled by a Biomimetic Targeting Nanosystem for Cholangiocarcinoma.
Advanced science (Weinheim, Baden-Wurttemberg, Germany)
Targeted delivery of glutamine metabolism inhibitors holds promise for cholangiocarcinoma therapy, yet effective delivery vehicles remain a challenge. This study reports the development of a biomimetic nanosystem, termed R-CM@MSN@BC, integrating mesoporous organosilicon nanoparticles with reactive oxygen species-responsive diselenide bonds for controlled release of the glutamine metabolism inhibitor bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl) ethyl sulfide (BPTES) and the photosensitizer Ce6. Erythrocyte membrane coating, engineered with Arg-Gly-Asp (RGD) peptides, not only enhanced biocompatibility but also improved tumor targeting and tissue penetration. Upon laser irradiation, R-CM@MSN@BC executed both photodynamic and glutamine-metabolic therapies, inducing necroptosis in tumor cells and triggering significant immunogenic cell death. Time-of-flight mass cytometry analysis revealed that R-CM@MSN@BC can remodel the immunosuppressive tumor microenvironment by polarizing M1-type macrophages, reducing infiltration of M2-type and CX3CR1 macrophages, and decreasing T cell exhaustion, thereby increasing the effectiveness of anti-programmed cell death ligand 1 immunotherapy. This strategy proposed in this study presents a viable and promising approach for the treatment of cholangiocarcinoma.
10.1002/advs.202309203
Double-Layered Hollow Mesoporous Cuprous Oxide Nanoparticles for Double Drug Sequential Therapy of Tumors.
Advanced materials (Deerfield Beach, Fla.)
Cancer stem cells (CSCs) are one of the determinants of tumor heterogeneity and are characterized by self-renewal, high tumorigenicity, invasiveness, and resistance to various therapies. To overcome the resistance of traditional tumor therapies resulting from CSCs, a strategy of double drug sequential therapy (DDST) for CSC-enriched tumors is proposed in this study and is realized utilizing the developed double-layered hollow mesoporous cuprous oxide nanoparticles (DL-HMCONs). The high drug-loading contents of camptothecin (CPT) and all-trans retinoic acid (ATRA) demonstrate that the DL-HMCON can be used as a generic drug delivery system. ATRA and CPT can be sequentially loaded in and released from CPT3@ATRA3@DL-HMCON@HA. The DDST mechanisms of CPT3@ATRA3@DL-HMCON@HA for CSC-containing tumors are demonstrated as follows: 1) the first release of ATRA from the outer layer induces differentiation from CSCs with high drug resistance to non-CSCs with low drug resistance; 2) the second release of CPT from the inner layer causes apoptosis of non-CSCs; and 3) the third release of Cu from DL-HMCON itself triggers the Fenton-like reaction and glutathione depletion, resulting in ferroptosis of non-CSCs. This CPT3@ATRA3@DL-HMCON@HA is verified to possess high DDST efficacy for CSC-enriched tumors with high biosafety.
10.1002/adma.202313212
Employing Piezoelectric Mg-Doped Hydroxyapatite to Target Death Receptor-Mediated Necroptosis: A Strategy for Amplifying Immune Activation.
Advanced science (Weinheim, Baden-Wurttemberg, Germany)
Although immunogenic cell death (ICD) inducers evidently enhance the effectiveness of immunotherapy, their potential is increasingly restricted by the development of apoptosis resistance in tumor cells, poor immunogenicity, and low T-cell immune responsiveness. In this study, for the first time, piezoelectrically catalyzed Mg-doped hydroxyapatite (Mg-HAP) nanoparticles, which are coated with a mesoporous silica layer and loaded with ONC201 as an agonist to specifically target the death receptor DR5 on tumor cells, ultimately developing an Mg-HAP@MS/ONC201 nanoparticle (MHMO NP) system, are engineered. Owing to its excellent piezoelectric properties, MHMO facilitates the release of a significant amount of reactive oxygen species and Ca within tumor cells, effectively promoting the upregulation of DR5 expression and inducing tumor cell necroptosis to ultimately overcome apoptosis resistance. Concurrently, Mg released in the tumor microenvironment promotes CD8 T receptor activation in response to the antitumor immune reaction induced by ICD. Using RNA-seq analysis, it is elucidated that MHMO can activate the NF-κB pathway under piezoelectric catalysis, thus inducing M1-type macrophage polarization. In summary, a dual-targeting therapy system that targets both tumor cells and the tumor microenvironment under piezoelectric catalysis is designed. This system holds substantial potential for advancements in tumor immunotherapy.
10.1002/advs.202307130
pH-Responsive Upconversion Mesoporous Silica Nanospheres for Combined Multimodal Diagnostic Imaging and Targeted Photodynamic and Photothermal Cancer Therapy.
ACS nano
Photodynamic therapy (PDT) and photothermal therapy (PTT) have gained considerable attention as potential alternatives to conventional cancer treatments. However, these approaches remain limited by low solubility, poor stability, and inefficient targeting of many common photosensitizers (PSs) and photothermal agents (PTAs). To overcome the aforementioned limitations, we engineered biocompatible and biodegradable tumor-targeted upconversion nanospheres with imaging capabilities. The multifunctional nanospheres consist of a sodium yttrium fluoride core doped with lanthanides (ytterbium, erbium, and gadolinium) and the PTA bismuth selenide (NaYF:Yb/Er/Gd,BiSe) enveloped in a mesoporous silica shell that encapsulates a PS, chlorin e6 (Ce6), within its pores. NaYF:Yb/Er converts deeply penetrating near-infrared (NIR) light to visible light, which excites Ce6 to generate cytotoxic reactive oxygen species (ROS), while BiSe efficiently converts absorbed NIR light to heat. Additionally, Gd enables magnetic resonance imaging of the nanospheres. The mesoporous silica shell is coated with DPPC/cholesterol/DSPE-PEG to retain the encapsulated Ce6 and prevent serum protein adsorption and macrophage recognition that hinder tumor targeting. Finally, the coat is conjugated to the acidity-triggered rational membrane (ATRAM) peptide, which promotes specific and efficient internalization into malignant cells in the mildly acidic microenvironment of tumors. The nanospheres facilitated tumor magnetic resonance and thermal and fluorescence imaging and exhibited potent NIR laser light-induced anticancer effects and via combined ROS production and localized hyperthermia, with negligible toxicity to healthy tissue, hence markedly extending survival. Our results demonstrate that the ATRAM-functionalized, lipid/PEG-coated upconversion mesoporous silica nanospheres (ALUMSNs) offer multimodal diagnostic imaging and targeted combinatorial cancer therapy.
10.1021/acsnano.3c04564
Confining Prepared Ultrasmall Nanozymes Loading ATO for Lung Cancer Catalytic Therapy/Immunotherapy.
Advanced materials (Deerfield Beach, Fla.)
Nanozymes with inherent enzyme-mimicking catalytic properties combat malignant tumor progression via catalytic therapy, while the therapeutic efficacy still needs to be improved. In this work, ultrasmall platinum nanozymes (nPt) in a confined domain of a wormlike pore channel in gold nanobipyramidal-mesoporous silica dioxide nanocomposites, producing nanozyme carriers AP-mSi with photoenhanced peroxidase ability, are innovatively synthesized. Afterward, based on the prepared AP-mSi, a lung-cancer nanozymes probe (AP-HAI) is ingeniously produced by removing the SiO template, modifying human serum albumin, and loading atovaquone molecules (ATO) as well as IR780. Under NIR light irradiation, inner AuP and IR780 collaborate for photothermal process, thus facilitating the peroxidase-like catalytic process of H O . Additionally, loaded ATO, a cell respiration inhibitor, can impair tumor respiration metabolism and cause oxygen retention, hence enhancing IR780's photodynamic therapy (PDT) effectiveness. As a result, IR780's PDT and nPt nanozymes' photoenhanced peroxidase-like ability endow probes a high ROS productivity, eliciting antitumor immune responses to destroy tumor tissue. Systematic studies reveal that the obvious reactive oxygen species (ROS) generation is obtained by the strategy of using nPt nanozymes and reducing oxygen consumption by ATO, which in turn enables lung-cancer synergetic catalytic therapy/immunogenic-cell-death-based immunotherapy. The results of this work would provide theoretical justification for the practical use of photoenhanced nanozyme probes.
10.1002/adma.202303722
A Physiologically Responsive Nanocomposite Hydrogel for Treatment of Head and Neck Squamous Cell Carcinoma via Proteolysis-Targeting Chimeras Enhanced Immunotherapy.
Advanced materials (Deerfield Beach, Fla.)
Although immunotherapy has revolutionized oncotherapy, only ≈15% of head and neck squamous cell carcinoma (HNSCC) patients benefit from the current therapies. An immunosuppressive tumor microenvironment (TME) and dysregulation of the polycomb ring finger oncogene BMI1 are potential reasons for the failure. Herein, to promote immunotherapeutic efficacy against HNSCC, an injectable nanocomposite hydrogel is developed with a polymer framework (PLGA-PEG-PLGA) that is loaded with both imiquimod encapsulated CaCO nanoparticles (RC) and cancer cell membrane (CCM)-coated mesoporous silica nanoparticles containing a peptide-based proteolysis-targeting chimeras (PROTAC) for BMI1 and paclitaxel (PepM@PacC). Upon injection, this nanocomposite hydrogel undergoes in situ gelation, after which it degrades in the TME over time, releasing RC and PepM@PacC nanoparticles to respectively perform immunotherapy and chemotherapy. Specifically, the RC particles selectively manipulate tumor-associated macrophages and dendritic cells to activate a T-cell immune response, while CCM-mediated homologous targeting and endocytosis delivers the PepM@PacC particles into cancer cells, where endogenous glutathione promotes disulfide bond cleavage to release the PROTAC peptide for BMI1 degradation and frees the paclitaxel from the particle pores to elicit apoptosis meanwhile enhance immunotherapy. Thus, the nanocomposite hydrogel, which is designed to exploit multiple known vulnerabilities of HNSCC, succeeds in suppressing both growth and metastasis of HNSCC.
10.1002/adma.202210787
Biomimetic Macrophage Membrane-Camouflaged Nanoparticles Induce Ferroptosis by Promoting Mitochondrial Damage in Glioblastoma.
ACS nano
The increasing understanding of ferroptosis has indicated its role and therapeutic potential in cancer; however, this knowledge has yet to be translated into effective therapies. Glioblastoma (GBM) patients face a bleak prognosis and encounter challenges due to the limited treatment options available. In this study, we conducted a genome-wide CRISPR-Cas9 screening in the presence of a ferroptosis inducer (RSL3) to identify the key driver genes involved in ferroptosis. We identified ALOX15, a key lipoxygenase (LOX), as an essential driver of ferroptosis. Small activating RNA (saRNA) was used to mediate the expression of ALOX15 promoted ferroptosis in GBM cells. We then coated saALOX15-loaded mesoporous polydopamine (MPDA) with Angiopep-2-modified macrophage membranes (MMs) to reduce the clearance by the mononuclear phagocyte system (MPS) and increase the ability of the complex to cross the blood-brain barrier (BBB) during specific targeted therapy of orthotopic GBM. These generated hybrid nanoparticles (NPs) induced ferroptosis by mediating mitochondrial dysfunction and rendering mitochondrial morphology abnormal. In vivo, the modified MM enabled the NPs to target GBM cells, exert a marked inhibitory effect on GBM progression, and promote GBM radiosensitivity. Our results reveal ALOX15 to be a promising therapeutic target in GBM and suggest a biomimetic strategy that depends on the biological properties of MMs to enhance the in vivo performance of NPs for treating GBM.
10.1021/acsnano.3c07555
Dendritic Mesoporous Nanoparticles: Structure, Synthesis and Properties.
Angewandte Chemie (International ed. in English)
Recently, dendritic mesoporous silica nanoparticles with widespread applications have attracted great interest. Despite many publications (>800), the terminology "dendritic" is ambiguous. Understanding what possible "dendritic structures" are, their formation mechanisms and the underlying structure-property relationship is fundamentally important. With the advance of characterization techniques such as electron tomography, two types of tree-branch-like and flower-like structures can be distinguished, both described as "dendritic" in the literature. In this Review, we start with the definition of "dendritic", then provide critical analysis of reported dendritic silica nanoparticles according to their structural classification. We update the understandings of the formation mechanisms of two types of "dendritic" nanoparticles, highlighting how to control their structural parameters. Applications of dendritic mesoporous nanoparticles are also reviewed with a focus on the biomedical field, providing new insights into the structure-property relationship in this family of nanomaterials.
10.1002/anie.202112752
Nanoarchitectured Structure and Surface Biofunctionality of Mesoporous Silica Nanoparticles.
Kankala Ranjith Kumar,Han Ya-Hui,Na Jongbeom,Lee Chia-Hung,Sun Ziqi,Wang Shi-Bin,Kimura Tatsuo,Ok Yong Sik,Yamauchi Yusuke,Chen Ai-Zheng,Wu Kevin C-W
Advanced materials (Deerfield Beach, Fla.)
Mesoporous silica nanoparticles (MSNs), one of the important porous materials, have garnered interest owing to their highly attractive physicochemical features and advantageous morphological attributes. They are of particular importance for use in diverse fields including, but not limited to, adsorption, catalysis, and medicine. Despite their intrinsic stable siliceous frameworks, excellent mechanical strength, and optimal morphological attributes, pristine MSNs suffer from poor drug loading efficiency, as well as compatibility and degradability issues for therapeutic, diagnostic, and tissue engineering purposes. Collectively, the desirable and beneficial properties of MSNs have been harnessed by modifying the surface of the siliceous frameworks through incorporating supramolecular assemblies and various metal species, and through incorporating supramolecular assemblies and various metal species and their conjugates. Substantial advancements of these innovative colloidal inorganic nanocontainers drive researchers in promoting them toward innovative applications like stimuli (light/ultrasound/magnetic)-responsive delivery-associated therapies with exceptional performance in vivo. Here, a brief overview of the fabrication of siliceous frameworks, along with discussions on the significant advances in engineering of MSNs, is provided. The scope of the advancement in terms of structural and physicochemical attributes and their effects on biomedical applications with a particular focus on recent studies is emphasized. Finally, interesting perspectives are recapitulated, along with the scope toward clinical translation.
10.1002/adma.201907035
Mesoporous bioactive glass composition effects on degradation and bioactivity.
Schumacher M,Habibovic P,van Rijt S
Bioactive materials
Mesoporous bioactive glasses (MBGs) are promising materials for regenerative medicine, due to their favorable properties including bioactivity and degradability. These key properties, but also their surface area, pore structure and pore volume are strongly dependent on synthesis parameters and glass stoichiometry. However, to date no systematic study on MBG properties covering a broad range of possible compositions exists. Here, 24 MBG compositions in the SiO-CaO-PO system were synthesized by varying SiO (60-90 mol %), CaO and PO content (both 0 to 40 mol-%), while other synthesis parameters were kept constant. Mesopore characteristics, degradability and bioactivity were analysed. The results showed that, within the tested range of compositions, mesopore formation required a molar SiO content above 60% but was independent of CaO and PO content. While mesopore size did not depend on glass stoichiometry, mesopore arrangement was influenced by the SiO content. Specific surface area and pore volume were slightly altered by the SiO content. All materials were degradable; however, degradation as well as bioactivity, i.e. the ability to form a CaP mineral on the surface, depended on stoichiometry. Major differences were found in early surface reactions in simulated body fluid: where some MBGs induced direct hydroxyapatite crystallization, high release of calcium in others resulted in calcite formation. In summary, degradation and bioactivity, both key parameters of MBGs, can be controlled by glass stoichiometry over a broad range while leaving the unique structural parameters of MBGs relatively unaffected. This allows targeted selection of material compositions for specific regenerative medicine applications.
10.1016/j.bioactmat.2020.12.007
Injectable mesoporous bioactive glass/sodium alginate hydrogel loaded with melatonin for intervertebral disc regeneration.
Materials today. Bio
Intervertebral disc degeneration (IDD) is a major contributing factor to both lower back and neck pain. As IDD progresses, the intervertebral disc (IVD) loses its ability to maintain its disc height when subjected to axial loading. This failure in the weight-bearing capacity of the IVD is a characteristic feature of degeneration. Natural polymer-based hydrogel, derived from biological polymers, possesses biocompatibility and is able to mimic the structure of extracellular matrix, enabling them to support cellular behavior. However, their mechanical performance is relatively poor, thus limiting their application in IVD regeneration. In this study, we developed an injectable composite hydrogel, namely, Mel-MBG/SA, which is similar to natural weight-bearing IVD. Mesoporous bioactive glasses not only enhance hydrogels, but also act as carriers for melatonin (Mel) to suppress inflammation during IDD. The Mel-MBG/SA hydrogel further provides a mixed system with sustained Mel release to alleviate IL-1β-induced oxidative stress and relieve inflammation associated with IDD pathology. Furthermore, our study shows that this delivery system can effectively suppress inflammation in the rat tail model, which is expected to further promote IVD regeneration. This approach presents a novel strategy for promoting tissue regeneration by effectively modulating the inflammatory environment while harnessing the mechanical properties of the material.
10.1016/j.mtbio.2023.100731
Pharmacologic targeting of the p62 ZZ domain enhances both anti-tumor and bone-anabolic effects of bortezomib in multiple myeloma.
Haematologica
Multiple myeloma (MM) is a malignancy of plasma cells whose antibody secretion creates proteotoxic stress relieved by the N-end rule pathway, a proteolytic system that degrades N-arginylated proteins in the proteasome. When the proteasome is inhibited, protein cargo is alternatively targeted for autophagic degradation by binding to the ZZ-domain of p62/ sequestosome-1. Here, we demonstrate that XRK3F2, a selective ligand for the ZZ-domain, dramatically improved two major responses to the proteasome inhibitor bortezomib (Btz) by increasing: i) killing of human MM cells by stimulating both Btz-mediated apoptosis and necroptosis, a process regulated by p62; and ii) preservation of bone mass by stimulating osteoblast differentiation and inhibiting osteoclastic bone destruction. Co-administration of Btz and XRK3F2 inhibited both branches of the bimodal N-end rule pathway exhibited synergistic anti-MM effects on MM cell lines and CD138+ cells from MM patients, and prevented stromal-mediated MM cell survival. In mice with established human MM, co-administration of Btz and XRK3F2 decreased tumor burden and prevented the progression of MM-induced osteolytic disease by inducing new bone formation more effectively than either single agent alone. The results suggest that p62-ZZ ligands enhance the anti- MM efficacy of proteasome inhibitors and can reduce MM morbidity and mortality by improving bone health.
10.3324/haematol.2023.283787
Hierarchically Released Liquid Metal Nanoparticles for Mild Photothermal Therapy/Chemotherapy of Breast Cancer Bone Metastases via Remodeling Tumor Stromal Microenvironment.
Advanced healthcare materials
Currently, the treatment strategy for bone metastasis is mainly to inhibit the growth of tumor cells and the activity of osteoclasts, while ignoring the influence of the tumor stromal microenvironment (TSM) on the progression of bone metastasis. Herein, a dual-target liquid metal (LM)-based drug delivery system (DDS) with favorable photothermal performance is designed to spatially program the delivery of multiple therapeutic agents to enhance the treatment of bone metastasis through TSM remodeling. Briefly, mesoporous silicon-coated LM is integrated into zeolitic imidazolate framework-8 (ZIF-8) with both bone-seeking and tumor-targeting capacities. Curcumin (Cur), a tumor microenvironment modulator, is encapsulated into ZIF-8, and doxorubicin (DOX) is enclosed inside mesoporous silicon. Specific accumulation of the LM-based DDS in bone metastases first relieves the tumor stroma by releasing Cur in response to the acidic tumor microenvironment and then releases DOX deep into the tumor under near-infrared light irradiation. The combined strategy of the LM-based DDS and mild photothermal therapy has been shown to effectively restrain cross-talk between osteoclasts and tumor cells by inhibiting the secretion of transforming growth factor-β, degrading extracellular matrix components, and increasing infiltration of CD4 and CD8 T cells, which provides a promising strategy for the treatment of bone metastases.
10.1002/adhm.202301080
PDA-BPs integrated mussel-inspired multifunctional hydrogel coating on PPENK implants for anti-tumor therapy, antibacterial infection and bone regeneration.
Bioactive materials
Currently, many cancer patients with bone defects are still threatened by tumor recurrence, postoperative bacterial infection, and massive bone loss. Many methods have been studied to endow bone implants with biocompatibility, but it is difficult to find an implant material that can simultaneously solve the problems of anticancer, antibacterial and bone promotion. Here, a multifunctional gelatin methacrylate/dopamine methacrylate adhesive hydrogel coating containing 2D black phosphorus (BP) nanoparticle protected by polydopamine (pBP) is prepared by photocrosslinking to modify the surface of poly (aryl ether nitrile ketone) containing phthalazinone (PPENK) implant. The multifunctional hydrogel coating works in conjunction with pBP, which can deliver drug through photothermal mediation and kill bacteria through photodynamic therapy at the initial phase followed by promotion of osteointegration. In this design, photothermal effect of pBP control the release of doxorubicin hydrochloride loaded via electrostatic attraction. Meanwhile, pBP can generate reactive oxygen species (ROS) to eliminate bacterial infection under 808 nm laser. In the slow degradation process, pBP not only effectively consumes excess ROS and avoid apoptosis induced by ROS in normal cells, but also degrade into PO to promote osteogenesis. In summary, nanocomposite hydrogel coatings provide a promising strategy for treatment of cancer patients with bone defects.
10.1016/j.bioactmat.2023.04.020
Targeted Recruitment and Degradation of Estrogen Receptor α by Photothermal Polydopamine Nanoparticles for Breast Tumor Ablation.
Advanced healthcare materials
The major challenges of photothermal therapy (PTT) toward clinical application are the severe skin injury and inflammation response associated with high power laser irradiation. Herein, polydopamine nanoparticles (PDA-EST and PDA-RAL) targeted to estrogen receptor α (ERα) for efficient ablation of breast tumor under a low irradiation density of 0.1 W cm are reported. These nanoparticles are capable of recruiting ERα on their surface and induce a complete ERα degradation via localized heat. Owing to the ERα targetability, PDA-EST and PDA-RAL strongly suppress the proliferation of breast cancer cells without causing significant inflammation. This work provides a generalized method for enhancing PTT efficacy under low irradiation density.
10.1002/adhm.202200960
Metal Ion Augmented Mussel Inspired Polydopamine Immobilized 3D Printed Osteoconductive Scaffolds for Accelerated Bone Tissue Regeneration.
ACS applied materials & interfaces
Critical bone defects with a sluggish rate of auto-osteoconduction and imperfect reconstruction are motivators for the development of an alternate innovative approach for the regeneration of bone. Tissue engineering for bone regeneration signifies an advanced way to overcome this problem by creating an additional bone tissue substitute. Among different fabrication techniques, the 3D printing technique is obviously the most efficient and advanced way to fabricate an osteoconductive scaffold with a controlled porous structure. In the current article, the polycarbonate and polyester diol based polyurethane-urea (P12) was synthesized and 3D porous nanohybrid scaffolds (P12/TP-nHA) were fabricated using the 3D printing technique by incorporating the osteoconductive nanomaterial titanium phosphate adorned nanohydroxyapatite (TP-nHA). To improve the bioactivity, the surface of the fabricated scaffolds was modified with the immobilized biomolecule polydopamine (PDA) at room temperature. XPS study as well as the measurement of surface wettability confirmed the higher amount of PDA immobilization on TP-nHA incorporated nanohybrid scaffolds through the dative bone formation between the vacant d orbital of the incorporated titanium ion and the lone pair electron of the catechol group of dopamine. The incorporated titanium phosphate (TP) increased the tensile strength (53.1%) and elongation at break (96.8%) of the nanohybrid composite as compared to pristine P12. Moreover, the TP incorporated nanohybrid scaffold with calcium and phosphate moieties and a higher amount of immobilized active biomolecule improved the bioactivity, including the cell viability, cell proliferation, and osteogenic gene expression using hMSCs, of the fabricated nanohybrid scaffolds. A rat tibia defect model depicted that the TP incorporated nanohybrid scaffold with immobilized PDA enhanced the bone regeneration ability compared to the control sample without revealing any organ toxicity signifying the superior osteogenic bioactivity. Thus, a TP augmented polydopamine immobilized polyurethane-urea based nanohybrid 3D printed scaffold with improved physicochemical properties and osteogenic bioactivity could be utilized as an excellent advanced material for bone regeneration substitute.
10.1021/acsami.2c01657
Polydopamine Nanostructure-Enhanced Water Interaction with pH-Responsive Manganese Sulfide Nanoclusters for Tumor Magnetic Resonance Contrast Enhancement and Synergistic Ferroptosis-Photothermal Therapy.
ACS nano
Rational structure design benefits the development of efficient nanoplatforms for tumor theranostic application. In this work, a multifunctional polydopamine (PDA)-coated manganese sulfide (MnS) nanocluster was prepared. The polyhydroxy structure of PDA enhanced the water interaction with pH-responsive MnS nanoclusters via hydrogen bonds. At pH 5.5 conditions, the spin-lattice relaxation rate of MnS nanoclusters dramatically increased from 5.76 to 19.33 mM·s after the PDA coating, which can be beneficial for efficient tumor magnetic resonance imaging. In addition, PDA endowed MnS nanoclusters with excellent biocompatibility and good photothermal conversion efficiency, which can be used for efficient tumor photothermal therapy (PTT). Furthermore, MnS nanoclusters possess the ability to release HS in the acidic tumor microenvironment, effectively inhibiting mitochondrial respiration and adenosine triphosphate production. As a result, the expression of heat shock protein was obviously reduced, which can reduce the resistance of tumor cells to photothermal stimulation and enhance the efficacy of PTT. The released Mn also displayed efficient peroxidase and glutathione oxidase-like activity, effectively inducing tumor cell ferroptosis and apoptosis at the same time. Therefore, this nanoplatform could be a potential nanotheranostic for magnetic resonance contrast enhancement and synergistic ferroptosis-PTT of tumors.
10.1021/acsnano.3c10249
Shape-Regulated Photothermal-Catalytic Tumor Therapy Using Polydopamine@Pt Nanozymes with the Elicitation of an Immune Response.
Small (Weinheim an der Bergstrasse, Germany)
Recently, nanozyme-based photothermal-catalytic therapy has emerged as a promising strategy for antitumor treatment. Extensive research has focused on optimizing the catalytic activity and photothermal conversion performance of nanozymes through size, morphology, and surface property regulations. However, the biological effects of nanozymes, such as cellular uptake and cytotoxicity, resulting from their physicochemical properties, remain largely unexplored. In this study, two types of polydopamine/platinum (PDA@Pt) nanozymes, flower-like (FPDA@Pt) and mesoporous spherical-like (MPDA@Pt), to comprehensively compare their enzyme-mimicking activity, photothermal conversion capacity, and antitumor efficiency are designed. These findings revealed that FPDA@Pt exhibited superior peroxidase-like activity and higher photothermal conversion efficiency compared to MPDA@Pt. This led to enhanced production of reactive oxygen species (ROS) and increased heat generation at tumor sites. Importantly, it is observed thatthe flower-like structure of FPDA@Pt facilitated enhanced cellular uptake, leading to an increased accumulation of nanozymes within tumor cells. Furthermore, the light irradiation on tumors also triggered a series of anti-tumor immune responses, further enhancing the therapeutic efficacy. This work provides a possible design orientation for nanozyme-based photothermal-catalytic tumor therapy, highlighting the importance of considering the physicochemical properties of nanozymes to optimize their therapeutic potential in antitumor strategies.
10.1002/smll.202309096
Copper Deposition in Polydopamine Nanostructure to Promote Cuproptosis by Catalytically Inhibiting Copper Exporters of Tumor Cells for Cancer Immunotherapy.
Small (Weinheim an der Bergstrasse, Germany)
Cuproptosis is an emerging programmed cell death, displaying great potential in cancer treatment. However, intracellular copper content to induce cuproptosis is unmet, which mainly ascribes to the intracellular pumping out equilibrium mechanism by copper exporter ATP7A and ATP7B. Therefore, it is necessary to break such export balance mechanisms for desired cuproptosis. Mediated by diethyldithiocarbamate (DTC) coordination, herein a strategy to efficiently assemble copper ions into polydopamine nanostructure (PDA-DTC/Cu) for reprogramming copper metabolism of tumor is developed. The deposited Cu can effectively trigger the aggregation of lipoylated proteins to induce cuproptosis of tumor cells. Beyond elevating intracellular copper accumulation, PDA-DTC/Cu enables to break the balance of copper metabolism by disrupting mitochondrial function and restricting the adenosine triphosphate (ATP) energy supply, thus catalytically inhibiting the expressions of ATP7A and ATP7B of tumor cells to enhance cuproptosis. Meanwhile, the killed tumor cells can induce immunogenic cell death (ICD) to stimulate the immune response. Besides, PDA-DTC/Cu NPs can promote the repolarization of tumor-associated macrophages (TAMs ) to relieve the tumor immunosuppressive microenvironment (TIME). Collectively, PDA-DTC/Cu presented a promising "one stone two birds" strategy to realize copper accumulation and inhibit copper export simultaneously to enhance cuproptosis for 4T1 murine breast cancer immunotherapy.
10.1002/smll.202308565
A facile boronophenylalanine modified polydopamine dual drug-loaded nanoparticles for enhanced anti-tumor immune response in hepatocellular carcinoma comprehensive treatment.
Biomaterials
Hepatocellular carcinoma (HCC) has an insidious onset and high malignancy. Most patients have progressed to intermediate and advanced stages by the time of diagnosis, and the long-term efficacy of traditional treatments is not satisfactory. Immunotherapy has shown great promise in the treatment of HCC in recent years; however, the low immunogenicity and severe immunosuppressive tumor microenvironment result in a low response rate to immunotherapy in HCC patients. Therefore, it is of great significance to improve the immunogenicity of HCC and thus enhance its sensitivity to immunotherapy. Here, we prepared the boronophenylalanine-modified dual drug-loaded polydopamine nanoparticles by a facile method. This system used boronophenylalanine-modified polydopamine nanoparticles as a delivery vehicle and photothermal material for the chemotherapeutic drug doxorubicin and the immune agonist CpG oligodeoxynucleotides (CpG-ODN), with both active targeting and lysosomal escape functions. The cancer cells are rapidly killed by photothermal treatment, and then chemotherapy is used to further kill cancer cells that are inadequately treated by photothermal treatment. The combination of photothermal-chemotherapy synergistically induces the release of relevant antigens from tumor cells, thus initiating anti-tumor immunity; and then cooperates with CpG-ODN to trigger a powerful anti-tumor immune memory effect, potently and durably inhibiting HCC recurrence.
10.1016/j.biomaterials.2023.122435
Photothermal Fibrous Chitosan/Polydopamine Sponge for Intraoperative Hemostasis and Prevention of Tumor Recurrence in Hepatocellular Carcinoma Resection.
Advanced science (Weinheim, Baden-Wurttemberg, Germany)
Hepatectomy, a surgical procedure for liver cancer, is often plagued by high recurrence rates worldwide. The recurrence of liver cancer is primarily attributed to microlesions in the liver, changes in the immune microenvironment, and circulating tumor cells in the bloodstream. To address this issue, a novel intervention method that combines intraoperative hemostasis with mild photothermal therapy is proposed, which has the potential to ablate microlesions and improve the immune microenvironment simultaneously. Specifically, the integrated strategy is realized based on the fibrous chitosan/polydopamine sponge (CPDS), which is constructed from shearing-flow-induced oriented hybrid chitosan fibers and subsequent self-assembly of polydopamine. The CPDS demonstrates high elasticity, excellent water absorption, and photothermal conversion performance. The results confirm the efficient hemostatic properties of the fibrous CPDS in various bleeding models. Notably, in subcutaneous and orthotopic postoperative recurrence and metastasis models of hepatocellular carcinoma, the fibrous CPDS significantly inhibits local tumor recurrence and distant metastasis. Moreover, the combination with lenvatinib can substantially enhance the antitumor effect. This comprehensive treatment strategy offers new insights into hepatectomy of liver cancer, representing a promising approach for clinical management.
10.1002/advs.202304053
Programmed Cascade Polydopamine Nanoclusters for Pyroptosis-Based Tumor Immunotherapy.
Small (Weinheim an der Bergstrasse, Germany)
Pyroptosis, an inflammatory cell death, plays a pivotal role in activating inflammatory response, reversing immunosuppression and enhancing anti-tumor immunity. However, challenges remain regarding how to induce pyroptosis efficiently and precisely in tumor cells to amplify anti-tumor immunotherapy. Herein, a pH-responsive polydopamine (PDA) nanocluster, perfluorocarbon (PFC)@octo-arginine (R)-1-Hexadecylamine (He)-porphyrin (Por)@PDA-gambogic acid (GA)-cRGD (R-P@PDA-GC), is rationally design to augment phototherapy-induced pyroptosis and boost anti-tumor immunity through a two-input programmed cascade therapy. Briefly, oxygen doner PFC is encapsulated within R linked photosensitizer Por and He micelles as the core, followed by incorporation of GA and cRGD peptides modified PDA shell, yielding the ultimate R-P@PDA-GC nanoplatforms (NPs). The pH-responsive NPs effectively alleviate hypoxia by delivering oxygen via PFC and mitigate heat resistance in tumor cells through GA. Upon two-input programmed irradiation, R-P@PDA-GC NPs significantly enhance reactive oxygen species production within tumor cells, triggering pyroptosis via the Caspase-1/GSDMD pathway and releasing numerous inflammatory factors into the TME. This leads to the maturation of dendritic cells, robust infiltration of cytotoxic CD8 T and NK cells, and diminution of immune suppressor Treg cells, thereby amplifying anti-tumor immunity.
10.1002/smll.202401397
Scaffold 3D-Printed from Metallic Nanoparticles-Containing Ink Simultaneously Eradicates Tumor and Repairs Tumor-Associated Bone Defects.
Lin Huimin,Shi Shanwei,Lan Xinyue,Quan Xiaolong,Xu Qinqin,Yao Guangyu,Liu Jia,Shuai Xintao,Wang Chong,Li Xiang,Yu Meng
Small methods
Bone metastasis occurs in about 70% of breast cancer patients. The surgical resection of metastatic tumors often leads to bone erosion and destruction, which greatly hinders the treatment and prognosis of breast cancer patients with bone metastasis. Herein, a bifunctional scaffold 3D-printed from nanoink is fabricated to simultaneously eliminate the tumor cells and repair the tumor-associated bone defects. The metallic polydopamine (PDA) nanoparticles (FeMg-NPs) may effectively load and sustainably release the metal ions Fe and Mg in situ. Fe exerts a chemodynamic therapy to synergize with the photothermal therapy induced by PDA with effective photothermal conversion under NIR laser, which efficiently eliminates the bone-metastatic tumor. Meanwhile, the sustained release of osteoinductive Mg from the bony porous 3D scaffold enhances the new bone formation in the bone defects. Taken together, the implantation of scaffold (FeMg-SC) 3D-printed from the FeMg-NPs-containing nanoink provides a novel strategy to simultaneously eradicate bone-metastatic tumor and repair the tumor-associated bone defects.
10.1002/smtd.202100536
Smart-Responsive Multifunctional Therapeutic System for Improved Regenerative Microenvironment and Accelerated Bone Regeneration via Mild Photothermal Therapy.
Advanced science (Weinheim, Baden-Wurttemberg, Germany)
The treatment of bone defects remains a substantial clinical challenge due to the lack of spatiotemporal management of the immune microenvironment, revascularization, and osteogenic differentiation. Herein, deferoxamine (DFO)-loaded black phosphorus nanosheets decorated by polydopamine layer are prepared (BPPD) and compounded into gelatin methacrylate/sodium alginate methacrylate (GA) hybrid hydrogel as a smart-responsive therapeutic system (GA/BPPD) for accelerated bone regeneration. The BPPD nanocomposites served as bioactive components and near-infrared (NIR) photothermal agents, which conferred the hydrogel with excellent NIR/pH dual-responsive properties, realizing the stimuli-responsive release of DFO and PO during bone regeneration. Under the action of NIR-triggered mild photothermal therapy, the GA/BPPD hydrogel exhibited a positive effect on promoting osteogenesis and angiogenesis, eliminating excessive reactive oxygen species, and inducing macrophage polarization to the M2 phenotype. More significantly, through macrophage M2 polarization-induced osteoimmune microenvironment, this hydrogel platform could also drive functional cytokine secretion for enhanced angiogenesis and osteogenesis. In vivo experiments further demonstrated that the GA/BPPD system could facilitate bone healing by attenuating the local inflammatory response, increasing the secretion of pro-healing factors, stimulating endogenous cell recruitment, and accelerating revascularization. Collectively, the proposed intelligent photothermal hydrogel platform provides a promising strategy to reshape the damaged tissue microenvironment for augmented bone regeneration.
10.1002/advs.202304641
Polydopamine-Mediated Immunomodulatory Patch for Diabetic Periodontal Tissue Regeneration Assisted by Metformin-ZIF System.
ACS nano
An essential challenge in diabetic periodontal regeneration is achieving the transition from a hyperglycemic inflammatory microenvironment to a regenerative one. Here, we describe a polydopamine (PDA)-mediated ultralong silk microfiber (PDA-mSF) and metformin (Met)-loaded zeolitic imidazolate framework (ZIF) incorporated into a silk fibroin/gelatin (SG) patch to promote periodontal soft and hard tissue regeneration by regulating the immunomodulatory microenvironment. The PDA-mSF endows the patch with a reactive oxygen species (ROS)-scavenging ability and anti-inflammatory activity, reducing the inflammatory response by suppressing M1 macrophage polarization. Moreover, PDA improves periodontal ligament reconstruction via its cell affinity. Sustained release of Met from the Met-ZIF system confers the patch with antiaging and immunomodulatory abilities by activating M2 macrophage polarization to secrete osteogenesis-related cytokines, while release of Zn also promotes bone regeneration. Consequently, the Met-ZIF system creates a favorable microenvironment for periodontal tissue regeneration. These features synergistically accelerate diabetic periodontal bone and ligament regeneration. Thus, our findings offer a potential therapeutic strategy for hard and soft tissue regeneration in diabetic periodontitis.
10.1021/acsnano.3c02407
Artificial Nonenzymatic Antioxidant MXene Nanosheet-Anchored Injectable Hydrogel as a Mild Photothermal-Controlled Oxygen Release Platform for Diabetic Wound Healing.
ACS nano
Hypoxia, excessive reactive oxygen species (ROS), impaired angiogenesis, lasting inflammation, and bacterial infection, are key problems impeding diabetic wound healing. Particularly, controllable oxygen release and ROS scavenging capacities are critical during the wound healing process. Here, an injectable hydrogel based on hyaluronic acid--dopamine (HA-DA) and polydopamine (PDA) coated TiC MXene nanosheets is developed catalytically cross-linked by an oxyhemoglobin/hydrogen (HbO/HO) system combined with mild photothermal stimulation for diabetic wound healing. HbO not only acts as a horseradish peroxidase-like to catalyze the hydrogel formation but also as an oxygen carrier to controllably release oxygen when activated by the mild heat produced from near-infrared (NIR) irradiation. Specifically, HbO can provide oxygen repeatedly by binding oxygen in the air when the NIR is off. The stable photoresponsive heating behavior of MXene ensures the repeatable oxygen release. Additionally, artificial nonenzymatic antioxidant MXene nanosheets are proposed to scavenge excessive reactive nitrogen species and ROS including HO, O, and OH, keeping the intracellular redox homeostasis and alleviating oxidative stress, and eradicate bacteria to avoid infection. The antioxidant and antibacterial abilities of MXene are further improved by PDA coating, which also promotes the MXene nanosheets cross-linking into the network of the hydrogel. HA-DA molecules endow the hydrogel with the capacity to regulate macrophage polarization from M1 to M2 to achieve anti-inflammation. More importantly, the MXene-anchored hydrogel with multifunctions including tissue adhesion, self-healing, injectability, and hemostasis, combined with mild photothermal stimulation, greatly promotes human umbilical vein endothelial cell proliferation and migration and notably facilitates infected diabetic wound healing.
10.1021/acsnano.1c10575