Biodegradable Nanoplatform Research Articles

Glutathione-responsive biodegradable nanohybrid for cancer photoacoustic imaging and gas-assisted photothermal therapy

Photothermal therapy (PTT), particularly in the near-infrared-II (NIR-II) range, has attracted widespread attention over the past years. However, the accompanied inflammatory responses can result in undesirable side effects and contribute to treatment ineffectiveness. Herein, we introduced a novel biodegradable nanoplatform (CuS/HMON-PEG) capable of PTT and hydrogen sulfide (H2S) generation, aimed at modulating inflammation for improved cancer treatment outcomes. The embedded ultrasmall copper sulphide (CuS) nanodots (1–2 nm) possessed favorable photoacoustic imaging (PAI) and NIR-II photothermal capabilities, rendering CuS/HMON-PEG an ideal phototheranostic agent. Upon internalization by 4T1 cancer cells, the hollow mesoporous organosilica nanoparticle (HMON) component could react with the overproduced glutathione (GSH) to produce H2S. In addition to the anticipated photothermal tumor ablation and H2S-induced mitochondrial dysfunction, the anti-inflammatory regulation was also been demonstrated by the downregulation of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1beta (IL-1β). More importantly, the modulation of inflammation also promoted wound healing mediated by PTT. This work not only presents a H2S-based nanomodulator to boost NIR-II PTT but also provides insights into the construction of novel organic/inorganic hybrid nanosystems.

A redox homeostasis disruptor based on a biodegradable nanoplatform for ultrasound (US) imaging-guided high-performance ferroptosis therapy of tumors

ABSTRACT The synergistic disruption of intracellular redox homeostasis through the combination of ferroptosis/gas therapy shows promise in enhancing the antitumor efficacy. However, the development of an optimal delivery system encounters significant challenges, including effective storage, precise delivery, and controlled release of therapeutic gas. In this study, we propose the utilization of a redox homeostasis disruptor that is selectively activated by the tumor microenvironment (TME), in conjunction with our newly developed nanoplatforms (MC@HMOS@Au@RGD), for highly efficient ferroptosis therapy of tumors. The TME-triggered degradation of HMOS initiates the release of MC and AuNPs from the MC@HMOS@Au@RGD nanoplatform. The released MC subsequently reacts with endogenous hydrogen peroxide (H2O2) and H+ to enable the on-demand release of CO gas, leading to mitochondrial damage. Simultaneously, the released AuNPs exhibit GOx-like activity, catalyzing glucose to generate gluconic acid and H2O2. This process not only promotes the decomposition of MnCO to enhance CO production but also enhances the Fenton-like reaction between Mn2+ and H2O2, generating ROS through the modulation of the H+ and H2O2-enriched TME. Moreover, the generation of CO bubbles enables the monitoring of the ferroptosis treatment process through ultrasound (US) imaging. The efficacy of our prepared MC@HMOS@Au@RGD disruptors in ferroptosis therapy is validated through both in vitro and in vivo experiments.

HAase/GSH dual-responsive mesoporous organosilica nanoparticles for synergistic photodynamic/photothermal/pharmacological antibacterial therapy

A dual-responsive, biodegradable nanoplatform based on mesoporous organosilica nanoparticles, is reported. It enables multimodal synergistic antibacterial therapy of photodynamic/photothermal/pharmacological therapy.

Improved antitumor activity through a tyramidyl maslinic acid derivative. Design and validation as drug-loaded electrospun polymeric nanofibers

Among the most harmful tumors detected in the human body, such as breast, colon, brain or pancreas, breast (BC) and colorectal cancer (CRC) are the first and third most frequent cancer worldwide, respectively. The current existing chemotherapeutic treatments present serious side effects due to their intravenous administration can induce cytotoxicity in healthy cells. Thus, new treatment methods based on drug-loaded polymeric nanofibers (NFs) have gained significant potential for their use in localized cancer chemotherapy. Here, a deep in vitro comparative analysis between maslinic acid (MA) and a tyramine-maslinic acid (TMA) derivative is initially performed. This analysis includes a proliferation, and a cell cycle assay, and a genotoxicity, antiangiogenic and apoptosis study. Then, the TMA derivative has been incorporated into electrospun polymeric NFs obtaining an implantable dressing material with antitumor activity. Two types of patches containing TMA-loaded polymeric NFs of poly(caprolactone) (PCL), and a mixture of polylactic acid/poly(4-vinylpyridine) (PLA/PVP) were fabricated by the electrospinning technique. The characterization of the drug-loaded NFs showed an encapsulation capacity of 0.027 mg TMA/mg PCL and 0.024 mg TMA/mg PLA/PVP. Then, the cytotoxic activity of both polymeric systems was tested in CRC (T84), BC (MCF-7) and a no tumor (L929) cell lines exposed to TMA-loaded NFs and blank NFs for 48 h. Moreover, cell cycle assay, genotoxicity, angiogenesis and apoptosis tests were carried out to study the mechanism of action of TMA. Blank NFs showed no-toxicity in all cell lines tested and both drug-loaded NFs significantly reduced cell proliferation (relative proliferation of ≈44 % and ≈25 % respectively). Therefore, TMA was less genotoxic than maslinic acid (MA), and reduced VEGFA expression in MCF-7 cells (1.32 and 2.12-fold for MA and TMA respectively). These results showed that TMA-loaded NFs could constitute a promising biocompatible and biodegradable nanoplatform for the local treatment of solid tumors such as CRC or BC.

Biomimetic nanoplatform with anti-inflammation and neuroprotective effects for repairing spinal cord injury in mice

Regeneration in the therapeutics of spinal cord injury (SCI) remains a challenge caused by the hyperinflammation microenvironment. Nanomaterials-based treatment strategies for diseases with excellent therapeutic efficacy are actively pursued. Here, we develop biodegradable poly (lactic-co-glycolic acid) nanoparticles (PLGA) obtained by loading celastrol (pCel) for SCI thrapy. Cel, as an antioxidant drug, facilitated reactive oxygen species (ROS) scavenging, and decreased the generation of pro-inflammatory cytokines. To facilitate its administration, pCel is formulated into microspheres by oil-in-water (O/W) emulsion/solvent evaporation technique. The constructed pCel can induced polarization of macrophages and obviously improved lipopolysaccharide (LPS) and interferon-γ (IFN-γ)-induced mitochondrial dysfunction, and increased neurite length in PC12 cells and primary neurons. In vivo experiments revealed that pCel regulated the phenotypic polarization of macrophages, prevented the release of pro-inflammatory cytokines, promoted myelin regeneration and inhibited scar tissue formation, and further improve motor function. These findings indicated that the neuroprotective effect of this artificial biodegradable nanoplatform is benefit for the therapy of SCI. This research opens an exciting perspective for the application of SCI treatment and supports the clinical significance of pCel.

Multifunctional Oxygen-Generating Nanoflowers for Enhanced Tumor Therapy.

Sonodynamic therapy (SDT) and chemotherapy have received great attention as effective methods for tumor treatment. However, the inherent hypoxia of the tumor greatly hinders its therapeutic efficacy. In this work, a tumor microenvironment-responsive biodegradable nanoplatform SiO2-MnO2-PEG-Ce6&DOX (designated as SMPC&D) is fabricated by encapsulating manganese oxide (MnO2) into silica nanoparticles and anchoring poly(ethylene glycol) (PEG) onto the surface for tumor hypoxia relief and delivery, then loaded with sonosensitizer Chlorin e6 (Ce6) and chemotherapeutic drug doxorubicin (DOX) for hypoxic tumor treatment. We evaluated the physicochemical properties of SMPC&D nanoparticles and the tumor therapeutic effects of chemotherapy and SDT under ultrasound stimulation in vitro and in vivo. After endocytosis by tumor cells, highly expressed glutathione (GSH) triggers biodegradation of the nanoplatform and MnO2 catalyzes hydrogen peroxide (H2O2) to generate oxygen (O2), thereby alleviating tumor hypoxia. Depleting GSH and self-supplying O2 effectively improve the SDT efficiency both in vitro and in vivo. Ultrasonic stimulation promoted the release and cellular uptake of chemotherapy drugs. In addition, the relieved hypoxia reduced the efflux of chemotherapy drugs by downregulating the expression of the P-gp protein, which jointly improved the effect of chemotherapy. This study demonstrates that the degradable SMPC&D as a therapeutic agent can achieve efficient chemotherapy and SDT synergistic therapy for hypoxic tumors.

Biodegradable mesoporous Co3O4 based nanocarriers with intrinsic lung carcinoma suppression for NIR II fluorescence bioimaging and photothermal augmented photodynamic therapy

As the highest prevalence and mortality, malignant lung carcinoma is still regarded to be an unabating cancer until now. Besides, mesoporous nanocarrier-based therapeutics delivery system has drawn plenty of attention and Co3O4 nanoparticles have been demonstrated intrinsic Fenton-like activity which is much higher than analogous synthesized Fe3O4. In this work, in order to precisely diagnose and effectively eliminate lung tumor cells, we have synthesized mesoporous hollowed Co3O4 nanocarriers with ICG loading and surface grafting of RGD peptides. We have demonstrated that the biodegradable nanoplatform is a promising NIR II fluorescent contrast agent for accurately delineating tumor counters and phototheranostic agent with photo-heat conversion efficiency as ∼59.93% under 808 nm light exposure. More importantly, the corresponded hyperthymia progressively potentiates the ROS production via Co ions catalyzation. Our Co-based nanocomposite could efficaciously suppress the tumorigenesis both in vitro and in vivo accompanied by 808 nm laser illumination. In summary, all data highlights the potency of biodegradable Co-based mesoporous nanocarriers as contrast agents for multimodal imaging and photothermal augmented ROS amplification for efficient lung tumor inhibition.

Multifunctional biodegradable nanoplatform based on oxaliplatin prodrug cross-linked mesoporous polydopamine for enhancing cancer synergetic therapy

Multifunctional biodegradable nanoplatform based on oxaliplatin prodrug cross-linked mesoporous polydopamine for enhancing cancer synergetic therapy

Biodegradable nanoplatform upregulates tumor microenvironment acidity for enhanced cancer therapy via synergistic induction of apoptosis, ferroptosis, and anti-angiogenesis

Chemodynamic therapy of cancer is limited by insufficient endogenous H2O2 generation and acidity in the tumor microenvironment (TME). Herein, we developed a biodegradable theranostic platform (pLMOFePt-TGO) involving composite of dendritic organosilica and FePt alloy, loaded with tamoxifen (TAM) and glucose oxidase (GOx), and encapsulated by platelet-derived growth factor-B (PDGFB)-labeled liposomes, that effectively uses the synergy among chemotherapy, enhanced chemodynamic therapy (CDT), and anti-angiogenesis. The increased concentration of glutathione (GSH) present in the cancer cells induces the disintegration of pLMOFePt-TGO, releasing FePt, GOx, and TAM. The synergistic action of GOx and TAM significantly enhanced the acidity and H2O2 level in the TME by aerobiotic glucose consumption and hypoxic glycolysis pathways, respectively. The combined effect of GSH depletion, acidity enhancement, and H2O2 supplementation dramatically promotes the Fenton-catalytic behavior of FePt alloys, which, in combination with tumor starvation caused by GOx and TAM-mediated chemotherapy, significantly increases the anticancer efficacy of this treatment. In addition, T2-shortening caused by FePt alloys released in TME significantly enhances contrast in the MRI signal of tumor, enabling a more accurate diagnosis. Results of in vitro and in vivo experiments suggest that pLMOFePt-TGO can effectively suppress tumor growth and angiogenesis, thus providing an exciting potential strategy for developing satisfactory tumor theranostics.

A Novel Biodegradable Nanoplatform for Tumor Microenvironments Responsive Bimodal Magnetic Resonance Imaging and Sonodynamic/Ion Interference Cascade Therapy

The unsatisfactory therapeutic effect and long-term adverse effect markedly prevent inorganic nanomaterials from clinical transformation. In light of this, we developed a novel biodegradable theranostic agent (MnCO3:Ho3+@DOX/Ca3(PO4)2@BSA, HMCDB) based on the sonosensitizer manganese carbonate (MnCO3) coating with calcium phosphate (Ca3(PO4)2) and simultaneously loaded it with the chemotherapeutic drug doxorubicin (DOX). Due to the mild acidity of the tumor microenvironment (TME), the Ca3(PO4)2 shell degraded first, releasing substantial quantities of calcium ions (Ca2+) and DOX. Meanwhile, with the ultrasound (US) irradiation, MnCO3 produced enough reactive oxygen species (ROS) to cause oxidative stress in the cells, resulting in accumulation of Ca2+. Consequently, the cascade effect significantly amplified the therapeutic effect. Importantly, the nanocomposite can be completely degraded and cleared from the body, demonstrating that it was a promising theranostic agent for tumor therapy. Furthermore, the doped holmium ions (Ho3+) and in situ generation of manganese ions (Mn2+) in TME endow the nanoagent with the ability for tumor-specific bimodality T1/T2-weighted magnetic resonance imaging (MRI). This novel nanoplatform with low toxicity and biodegradability holds great potential for cancer diagnosis and treatment.

Theranostic Hyaluronan Coated EDTA Modified Magnetic Mesoporous Silica Nanoparticles for Targeted Delivery of Cisplatin

One of the eminent capabilities of nanoparticles in drug delivery is active targeting. Mesoporous silica nanoparticles (MSNs) are among the well-known nanocarriers, which have been utilized for gene and drug deliveries due to their particular physical and chemical properties. The present study aimed to introduce an engineered type of EDTA-modified Magnetic Mesoporous Silica Nanoparticles (MMSNs) with hyaluronan coating as a theranostic agent for delivery of an anti-cancer drug (cisplatin). EDTA was first applied as a ligand for platinum-based drug loading. The nanoparticles were synthesized in several steps. The properties of each step were characterized by various techniques such as Fourier transform infrared (FT-IR), X-Ray diffraction (XRD), vibrating sample magnetometer (VSM), and N2 adsorption/desorption. Morphology was also checked by field emission scanning electron microscopy (FE-SEM) and Transmission electron microscopy (TEM). In addition, loading capacity (LC) and loading efficiency, and in vivo release of cisplatin were analyzed through ICP-OES. Eventually, the plasma concentration profile and cisplatin pharmacokinetics parameters after intravenous administration of EDTA-MMSN @ HA were evaluated. The average particle diameters of prepared structure were approximate range of 70–100 nm. The profile release of cisplatin in acidic medium was faster in 72 h, which confirmed the pH-responsive behavior of the nanoparticles. As the results of cytotoxicity showed, coating with HA can improve the internalization of nanoparticles in cancer cells compared to normal cells. Finally, EDTA-MMSN @ HA can be introduced as a new favor biocompatible and biodegradable nanoplatform for targeted drug delivery which can improve pharmacokinetic parameters. Overall, this study successfully synthesized a novel multifunctional pH-responsive MSN for efficient drug delivery and magnetic resonance imaging.

Controlled Release of TGF-β3 for Effective Local Endogenous Repair in IDD Using Rat Model.

IntroductionIntervertebral disc (IVD) degeneration (IDD) is one of the most widespread musculoskeletal diseases worldwide and remains an intractable clinical challenge. Currently, regenerative strategies based on biomaterials and biological factors to facilitate IVD repair have been widely explored. However, the harsh microenvironment, such as increased ROS and acidity, of the degenerative region impedes the efficiency of IVD repair. Here, an intelligent biodegradable nanoplatform using hollow manganese dioxide (H-MnO2) was developed to modulate the degenerative microenvironment and release transforming growth factor beta-3 (TGF-β3), which may achieve good long-term therapeutic effects on needle puncture-induced IDD.MethodsSurface morphology and elemental analysis of the MnO2 nanoparticles (NPs) were performed by transmission electron microscopy and an energy-dispersive X-ray spectroscopy detector system, respectively. The biological effects of MnO2 loaded with TGF-β3 (TGF-β3/MnO2) on nucleus pulposus cells (NPCs) were assessed via cytoskeleton staining, EdU staining, qPCR and immunofluorescence. The efficacy of TGF-β3/MnO2 on needle puncture-induced IDD was further examined using MRI and histopathological and immunohistochemical staining.ResultsThe MnO2 NPs had a spherical morphology and hollow structure that dissociated in the setting of a low pH and H2O2 to release loaded TGF-β3 molecules. In the oxidative stress environment, TGF-β3/MnO2 was superior to TGF-β3 and MnO2 NPs in the suppression of H2O2-induced matrix degradation, ROS, and apoptosis in NPCs. When injected into the IVDs of a rat IDD model, TGF-β3/MnO2 was able to prevent the degeneration and promote self-regeneration.ConclusionUse of an MnO2 nanoplatform for biological factors release to regulate the IDD microenvironment and promote endogenous repair may be an effective approach for treating IDD.

Simultaneous innate immunity activation and immunosuppression improvement by biodegradable nanoplatform for boosting antitumor chemo-immunotherapy

The suppressive immune microenvironment and the accompanying insufficient immune activation limit the effectiveness of chemotherapy. Here we constructed a nanoplatform (CA-1@HMnO2/HA-P-mAb) that can simultaneously activate innate immunity and relieve the immunosuppression to enhance the effect of immune-chemotherapy. The responsive cleavage of peptides (P) in the microenvironment established the basis for the separated and differentiated delivery to tumor cells and regulatory T cells (Tregs). The dropped antibodies (mAb) ran to Tregs to realize the efficacious remission of immunosuppression. Hollow mesoporous manganese dioxide nanoparticles (HMnO2 NPs) coated with hyaluronic acid (HA) could achieve tumor targeting and rapid glutathione-responsive degradation in tumor cells. Interestingly, benefiting from the collapse of the HMnO2 NPs, the large supply of curcumin analogue (CA-1) not only induced the apoptosis of cancer cells, but also improved their immunogenicity. Meanwhile, the released manganese could increase the production of inflammatory factors such as type I interferon by activating the stimulator of interferon genes pathway. The pro-inflammatory dominance and enhanced tumor immunogenicity resulting from the factors above, which further led to the maturation of dendritic cells (DCs) and the recruitment of cytotoxic T cells. CA-1@HMnO2/HA-P-mAb NPs completed the remodeling of the tumor immune microenvironment and had satisfactory anti-tumor effect on tumor-bearing mice. Therefore, this novel platform may offer therapeutic potential for cancer chemo-immunotherapy.

Engineering Macrophage Exosome Disguised Biodegradable Nanoplatform for Enhanced Sonodynamic Therapy of Glioblastoma.

Sonodynamic therapy (SDT) exhibits high tissue penetration and negligible radiation damage to normal tissues, and thus emerges as a promising cancer therapeutic modality for glioblastoma (GBM). However, the blood-brain barrier (BBB) and hypoxic microenvironment greatly limit the SDT efficiency. In this work, a biodegradable nanoplatform (termed as CSI) is fabricated by encapsulating catalase (CAT) into silica nanoparticles (CAT@SiO2 ) for tumor hypoxia relief, and then loaded with the sonosensitizer indocyanine green (ICG). Inspired by the ability of macrophages to cross the BBB, CSI is further coated with AS1411 aptamer-modified macrophage exosomes to form CSI@Ex-A, which possesses efficient BBB penetration and good cancer-cell-targeting capability. After tumor cell endocytosis, highly expressed glutathione (GSH) triggeres biodegradation of the nanoplatform and the released CAT catalyzes hydrogen peroxide (H2 O2 ) to produce O2 to relieve tumor hypoxia. The GSH depletion and O2 self-supplying effectively enhances the SDT efficiency both in vitro and in vivo. In addition, the resulting CSI@Ex-A exhibits good biocompatibility and long circulation time. These findings demonstrate that CSI@Ex-A may serve as a competent nanoplatform for GBM therapy, with potential for clinical translation.

Multifunctional liposomal nanostructure-mediated siRNA/bortezomib co-delivery for SHARP1 knockdown in MLL-AF6 acute myeloid leukemia

Acute myeloid leukemia (AML) has an extremely poor prognosis and high relapse and fatality rates. New therapeutic mechanisms for molecular targeted delivery are urgently needed to improve patient survival. In this study, we targeted the oncogenic transcription factor SHARP1 using multifunctional small interfering RNA (siRNA) and bortezomib (BTZ)-loaded cRGD-guided PEGylated cationic liposomal nanostructures to monitor their antileukemic activity in MLL-AF6 AML cells. Efficient siRNA/BTZ co-delivery by the nanostructures inhibited cell viability and the clonogenic growth as well as stimulated apoptosis of AML cells. We hypothesized that SHARP1 downregulation induced the accumulation of non-functional MLL-AF6, DOT1L, MEN1, and LEDGF fusion proteins, preventing MLL-AF complex formation and downregulating RAS-GTP and Bcl-2 expression, consequently triggering autophagy and apoptosis. The BTZ combination substantially augmented therapeutic synergy and enhanced autophagic and apoptotic events. Our findings demonstrate a state-of-the-art biodegradable nanoplatform for siRNA/BTZ co-delivery with targeted SHARP1 knockdown, demonstrating a potential therapeutic option for MLL-AF6 AML.

Synergistic interventional photothermal therapy and immunotherapy using an iron oxide nanoplatform for the treatment of pancreatic cancer

Pancreatic cancer (PC) is the most lethal malignancy due to its high metastatic ability and poor drug permeability. Here, a synergized interventional photothermal-immunotherapy strategy was developed with imaging guidance and temperature monitoring by magnetic resonance imaging (MRI) technique, for the local treatment of metastatic PC. A tumor microenvironment (TME)-responsive nanoplatform was fabricated via coating of DSPE-PEG and indocyanine green (ICG) onto imiquimod (IMQ) loaded amorphous iron oxide nanoparticles (IONs). This unique nanoplatform, IMQ@IONs/ICG, served as a contrast agent for MRI, a drug delivery vehicle for IMQ and ICG, and a catalyst for TME modulation. The biodegradable IMQ@IONs/ICG was also non-toxic, and improved the penetration of the loaded drugs in PC to maximize thermal ablation of the tumor and minimize damage to the surrounding healthy tissue. For the treatment of aggressive, metastatic Panc02-H7 pancreatic tumors in mice, ION-assisted MRI was employed to guide the administration of interventional photothermal therapy (IPTT) and monitor the temperature distribution in target tumor and surrounding tissue during treatment. The local IPTT treatment induced in situ immunogenic cell death (ICD), and, in combination with released IMQ, triggered a strong antitumor immunity, leading to decreased metastases and increased CD8+ in spleen and tumors. With precise local treatment and monitoring, treated primary tumors were completely eradicated, mesentery metastases were dramatically reduced, and the survival time was significantly prolonged, without damage to normal tissue and systemic autoimmunity. Overall, this synergistic strategy represents a promising approach to treat PC with significant potential for clinical applications. Statement of significancePancreatic cancer (PC) is one of the most lethal malignancies because it is non-permeable to drugs and highly metastatic. In this study, we designed a tumor microenvironment-responsive amorphous iron oxide nanoplatform (ION) to co-deliver photothermal agent (ICG) and toll-like-receptor-7 agonist (IMQ). This biodegradable nanoplatform IMQ@IONs/ICG improved the penetration of the loaded drugs in pancreatic tumor. With MR imaging guidance and temperature monitoring, the precise interventional photothermal therapy on mouse Panc02-H7 orthotopic tumors releases tumor antigens to initiate tumor-special immune responses, amplified by the released IMQ. Our results demonstrate that IMQ@IONs/ICG overcomes the obstacle of drug delivery to pancreatic tumors, and when combined with photothermal therapy, induces a systemic antitumor immunity to control metastatic tumors.

Biodegradable BiOCl platform for oxidative stress injury–enhanced chemodynamic/radiation therapy of hypoxic tumors

Various physiological characteristics of the tumor microenvironment (TME), such as hypoxia, overexpression of glutathione (GSH) and hydrogen peroxide (H2O2), and mild acidity, can severely reduce the efficacy of many cancer therapies. Altering the redox balance of the TME and increasing oxidative stress can accordingly enhance the efficacy of tumor therapy. Herein, we developed a bismuth-based Cu2+-doped BiOCl nanotherapeutic platform, BCHN, able to self-supply H2O2 for TME-regulated chemodynamic therapy (CDT) combined with sensitized radiotherapy (RT). BCHN released H2O2 and consumed GSH to degrade the composite in the slightly acidic TME, and generated hydroxyl radicals (•OH) via a Fenton-like reaction catalyzed by copper ions, to achieve oxidative stress-enhanced CDT. The Fenton-like reaction also catalyzed H2O2 to produce O2 to relieve tumor hypoxia, and combined with the X-ray-blocking property of bismuth to realize TME-enhanced radiotherapy. Synergistic CDT/RT has previously been shown to effectively inhibit tumor cell proliferation and achieve effective tumor control. The current results demonstrated a highly efficient multifunctional bio-degradable nanoplatform for oncotherapy. Statement of significanceTumor microenvironment-modulated synergy of radiotherapy and chemodynamic therapy is conducive to rapid tumor ablation. Based on this principle, we fabricated a biodegradable BiOCl-based nanocomposite, BCHN. By supplying H2O2, a Fenton-like reaction generated •OH and O2 catalyzed by copper ions, and consumed glutathione to biodegrade the composite. Overall, these actions increased tumor oxidative stress and realized the synergistic anti-tumor actions of chemodynamic therapy combined with bismuth-based sensitization radiotherapy. This strategy thus provides a unique approach to oncology therapy.

Glutathione-Responsive Biodegradable Nanoplatform with Endogenous Esterase-Triggered Nitric Oxide Release for Gas Therapy and Enhanced Chemotherapy.

The potential therapeutic effect of nitric oxide (NO) for cancers has received considerable attention as a "killer" that causes damage to mitochondria and DNA by oxidation or nitrosation. However, the fabrication of an intelligent and controllable NO release system has remained elusive in the desired location to realize selective cancer therapy. Herein, an intelligent endogenous esterase-triggered nitric oxide (NO) generator for synergetic cancer therapy is fabricated by integrating NO prodrug and doxorubicin (DOX) into a single glutathione (GSH)-responsive mesoporous silica nanoparticle (MPND). When the MPND is internalized into the cancer cell, the rupture of -S-S- bridges and the degradation of MPND occur in the tumor microenvironment with a high level of GSH, inducing the on-demand release of DOX. Importantly, the high endogenic esterase concentration can activate the prodrug to generate abundant NO, which further enhances the release performance of DOX. In vitro results verify that the release profiles of NO and DOX show the stimuli-responsive dependence of endogenic esterase and GSH, respectively, demonstrating the potential for on-demand release in the cancer cells. Consequently, MPND shows a high antitumor efficiency in MCF-7 cancer cells. Furthermore, using multicellular tumor spheroids to mimic in vivo experiment, MPND can enhance the tumor penetration and therapeutic effect for killing the deep tumor tissue at the central location. Therefore, the endogenous esterase-triggered NO nanogenerators may provide a potential alternative strategy to develop NO-relevant platforms for synergistic cancer therapy.

Microneedle-mediated delivery of MIL-100(Fe) as a tumor microenvironment-responsive biodegradable nanoplatform for O2-evolving chemophototherapy.

The low oxygen level in tumors significantly reduces the antitumor efficacy of photodynamic therapy (PDT). The provision of O2 and monomeric hydrophobic photosensitizers (PSs) under physiological conditions would greatly help to shrink malignant tumors. We take advantage of the high porosity and multifunctionality of metal-organic frameworks (MOFs) to fabricate a simple all-in-one nanoplatform mediated by microneedle delivery to achieve synergistic O2 evolution and chemophototherapy. An iron(III)-based MOF (MIL-100(Fe)) acted not only as a vehicle for the concurrent delivery of zinc phthalocyanine (ZnPc) and doxorubicin hydrochloride (Dox), but also to supply O2 by decomposing hydrogen peroxide (H2O2) in the tumor microenvironment via a Fenton-like reaction. In vitro and in vivo experiments indicated that the nanoplatform had excellent biocompatibility and exerted enhanced anticancer effects. The encapsulated drug was sustainably released from the nanoplatform skeleton in response to acidic tumor microenvironments. Moreover, upon 660 nm light irradiation, ZnPc effectively produced reactive oxygen species (ROS) due to the reduction of hypoxia by MIL-100(Fe). A microneedle technique was adopted to directly deliver the nanoplatform into superficial tumors rather than via systemic circulation. Hence, this study provides a new strategy for more efficient chemophototherapy of hypoxic superficial tumors.

Simultaneous Innate Immunity Activation and Immunosuppression Improvement by Biodegradable Nanoplatform for Boosting Antitumor Chemo-Immunotherapy

Simultaneous Innate Immunity Activation and Immunosuppression Improvement by Biodegradable Nanoplatform for Boosting Antitumor Chemo-Immunotherapy