Oral microbiome dysbiosis may be associated with intra cranial aneurysms.

BACKGROUND: Although the etiology of aneurysms remains elusive, recent advances in high-throughput sequencing technology and ongoing human microbiome investigations suggest a potential link between microbiome composition and the onset of various human diseases. OBJECTIVE: This study aimed to utilize high-throughput 16 S rRNA gene sequencing to analyze the oral flora bacterial profiles of individuals, comparing patients with intracranial aneurysms to a healthy control group. Importantly, we sought to identify differences in the oral microbiota and offer novel insights and methods for early diagnosis and identification of intracranial aneurysms. METHOD: Saliva samples were collected from 60 patients with cerebral aneurysms (case group) and 130 healthy individuals (control group). The V3-V4 region of the bacterial 16 S rRNA gene was amplified and sequenced using the HiSeq high-throughput sequencing platform to establish the bacterial profile. Sequencing data were analyzed using QIIME2 and Metastats software to compare composition differences and relative abundance at the phylum and genus levels in the oral microbiota of the two groups. RESULTS: Significant differences in oral microbiota composition were observed between patients in the case and control groups (P < 0.05). Genus-level identification highlighted key positions occupied by Eubacterium, Saccharimonadaceae, Rothia, Gemella, Streptococcus, Lactobacillales, Phocaeicola, Bacteroides, Saccharimonadales, and Abiotrophia. CONCLUSION: This study revealed noteworthy distinctions in the composition, abundance, and diversity of oral microbiota between intracranial aneurysm patients and healthy controls. These disparities suggest a potential correlation between oral microbiota and the development of intracranial aneurysms, offering new avenues for early diagnosis and intervention. However, limitations such as a small sample size, lack of prospective design, and absence of causal inference warrant further validation and exploration.

Multiblock Poly-ε-Caprolactones: One-Step Synthesis toward Programmable Properties.

Control of monomer sequence enables predictable structure-property relationships in versatile polymeric materials. The facile synthesis of multiblock copolymers (MBCPs) with controlled chain structure is highly challenging, particularly for those prepared via one-pot copolymerization of mixed monomers. Herein, poly-ε-caprolactone MBCPs, a series of thermoplastic elastomers with tailored thermal, mechanical, rheological, and degradable properties, are synthesized by Janus polymerization. Melting temperature, tensile strength, ductility, viscosity, and enzymatic degradability are governed by block length which is in turn dictated by the monomer-to-catalyst feed ratio. The relationships between the physicochemical properties and the architectures are investigated in detail.

Dual-Template Magnetic Molecularly Imprinted Polymer for Simultaneous Determination of Spot Urine Metanephrines and 3-Methoxytyramine for the Diagnosis of Pheochromocytomas and Paragangliomas.

A novel dual-template magnetic molecularly imprinted polymer (MMIP) was synthesized to extract normetanephrine (NMN), metanephrine (MN) and 3-methoxytyramine (3-MT) from spot urine samples. As the adsorbent of dispersive solid-phase extraction (d-SPE), the MMIP was prepared using dopamine and MN as dual templates, methacrylic acid as the functional monomer, ethylene glycol dimethacrylate as the crosslinking reagent and magnetic nanoparticles as the magnetic core. NMN, MN, 3-MT and creatinine (Cr) in spot urine samples were selectively enriched by d-SPE and detected by HPLC-fluorescence detection/ultraviolet detection. The peak area (A) ratios of NMN, MN and 3-MT to Cr were used for the diagnosis of pheochromocytomas and paragangliomas (PPGLs). The results showed that the adsorption efficiencies of MMIP for target analytes were all higher than 89.0%, and the coefficient variation precisions of intra-assay and inter-assay for the analytes were within 4.9% and 6.3%, respectively. The recoveries of the analytes were from 93.2% to 112.8%. The MMIP was still functional within 14 days and could be reused at least seven times. The d-SPE and recommended solid-phase extraction (SPE) were both used to pretreat spot urine samples from 18 PPGLs patients and 22 healthy controls. The correlation coefficients of ANMN/ACr and AMN/ACr between d-SPE and SPE were both higher than 0.95. In addition, the areas under the receiver operator curves for spot urine ANMN/ACr, AMN/ACr and plasma free NMN and MN were 0.975, 0.773 and 0.990, 0.821, respectively, indicating the two methods had the similar performances. The d-SPE method took only 20 min, which was effective in clinical application.

An efficient antimicrobial depot for infectious site-targeted chemo-photothermal therapy.

BACKGROUND: Silver and photothermal therapy (PTT) have been widely used for eradicating the drug-resistant bacteria. However, the risks of excess of silver for humans and the low efficiency of PTT still limit their in vivo therapeutic application. Integration of two distinctive bactericides into one entity is a promising platform to improve the efficiency of antimicrobial agents. RESULTS: In this study, a chemo-photothermal therapeutic platform based on polydopamine (PDA)-coated gold nanorods (GNRs) was developed. The PDA coating acquired high Ag+ ions loading efficiency and Cy5-SE fluorescent agent labeled glycol chitosan (GCS) conjugation (Ag+-GCS-PDA@GNRs). This platform became positively charged in the low pH environment of the abscess, allowing their accumulation in local infection site as revealed by thermal/florescence imaging. The loaded Ag+ ions was released in a pH-sensitive manner, resulting in selective Ag+ ions delivery to the abscess environment (pH ~ 6.3). More importantly, the ultralow dose of Ag+ ions could effectively damage the bacterial membrane, causing the permeability increase and the heat resistance reduction of the cell membrane, leading to the large improvement on bactericidal efficiency of PTT. On the other hand, the hyperthermia could trigger more Ag+ ions release, resulting in further improvement on bactericidal efficiency of chemotherapy. Combinational chemo-hyperthermia therapy of Ag+-GCS-PDA@GNRs could thoroughly ablate abscess and accelerate wound healing via a synergistic antibacterial effect. CONCLUSIONS: Our studies demonstrate that Ag+-GCS-PDA@GNRs is a robust and practical platform for use in chemo-thermal focal infection therapy with outstanding synergistic bacteria ablating.

Poly(N-phenylglycine)-Based Nanoparticles as Highly Effective and Targeted Near-Infrared Photothermal Therapy/Photodynamic Therapeutic Agents for Malignant Melanoma.

Malignant melanoma is a highly aggressive tumor resistant to chemotherapy. Therefore, the development of new highly effective therapeutic agents for the treatment of malignant melanoma is highly desirable. In this study, a new class of polymeric photothermal agents based on poly(N-phenylglycine) (PNPG) suitable for use in near-infrared (NIR) phototherapy of malignant melanoma is designed and developed. PNPG is obtained via polymerization of N-phenylglycine (NPG). Carboxylate functionality of NPG allows building multifunctional systems using covalent bonding. This approach avoids complicated issues typically associated with preparation of polymeric photothermal agents. Moreover, PNPG skeleton exhibits pH-responsive NIR absorption and an ability to generate reactive oxygen species, which makes its derivatives attractive photothermal therapy (PTT)/photodynamic therapy (PDT) dual-modal agents with pH-responsive features. PNPG is modified using hyaluronic acid (HA) and polyethylene glycol diamine (PEG-diamine) acting as the coupling agent. The resultant HA-modified PNPG (PNPG-PEG-HA) shows negligible cytotoxicity and effectively targets CD44-overexpressing cancer cells. Furthermore, the results of in vitro and in vivo experiments reveal that PNPG-PEG-HA selectively kills B16 cells and suppresses malignant melanoma tumor growth upon exposure to NIR light (808 nm), indicating that PNPG-PEG-HA can serve as a very promising nanoplatform for targeted dual-modality PTT/PDT of melanoma.

Hollow fiber membrane modification with functional zwitterionic macromolecules for improved thromboresistance in artificial lungs.

Respiratory assist devices seek optimized performance in terms of gas transfer efficiency and thromboresistance to minimize device size and reduce complications associated with inadequate blood biocompatibility. The exchange of gas with blood occurs at the surface of the hollow fiber membranes (HFMs) used in these devices. In this study, three zwitterionic macromolecules were attached to HFM surfaces to putatively improve thromboresistance: (1) carboxyl-functionalized zwitterionic phosphorylcholine (PC) and (2) sulfobetaine (SB) macromolecules (mPC or mSB-COOH) prepared by a simple thiol-ene radical polymerization and (3) a low-molecular weight sulfobetaine (SB)-co-methacrylic acid (MA) block copolymer (SBMAb-COOH) prepared by reversible addition-fragmentation chain transfer (RAFT) polymerization. Each macromolecule type was covalently immobilized on an aminated commercial HFM (Celg-A) by a condensation reaction, and HFM surface composition changes were analyzed by X-ray photoelectron spectroscopy. Thrombotic deposition on the HFMs was investigated after contact with ovine blood in vitro. The removal of CO2 by the HFMs was also evaluated using a model respiratory assistance device. The HFMs conjugated with zwitterionic macromolecules (Celg-mPC, Celg-mSB, and Celg-SBMAb) showed expected increases in phosphorus or sulfur surface content. Celg-mPC and Celg-SBMAb experienced rates of platelet deposition significantly lower than those of unmodified (Celg-A, >95% reduction) and heparin-coated (>88% reduction) control HFMs. Smaller reductions were seen with Celg-mSB. The CO2 removal rate for Celg-SBMAb HFMs remained comparable to that of Celg-A. In contrast, the rate of removal of CO2 for heparin-coated HFMs was significantly reduced. The results demonstrate a promising approach to modifying HFMs using zwitterionic macromolecules for artificial lung devices with improved thromboresistance without degradation of gas transfer.

The enhancement mechanisms of mucin and lactoferrin on α-amylase activity in saliva: Exploring the interactions using QCM-D and molecular docking.

α-Amylase activity differs between individuals and is influenced by dietary behavior and salivary constituents, but limited information is available on the relationship between α-amylase activity and saliva components. This study investigated the impact of salivary proteins on α-amylase activity, their various correlations, the effect of mucin (MUC5B and MUC7) and lactoferrin on the enzymatic kinetics of α-amylase, and the mechanisms of these interactions using the quartz crystal microbalance with dissipation (QCM-D) technique and molecular docking. The results showed that α-amylase activity was significantly correlated with the concentrations of MUC5B (R2 = 0.42, p < 0.05), MUC7 (R2 = 0.35, p < 0.05), and lactoferrin (R2 = 0.35, p < 0.05). An in vitro study demonstrated that α-amylase activity could be significantly increased by mucins and lactoferrin by decreasing the Michaelis constant (Km) of α-amylase. Moreover, the results from the QCM-D and molecule docking suggested that mucin and lactoferrin could interact with α-amylase to form stable α-amylase-mucin and α-amylase-lactoferrin complexes through hydrophobic interactions, electrostatic interactions, Van der Waals forces, and hydrogen bonds. In conclusion, these findings indicated that the salivary α-amylase activity depended not only on the α-amylase content, but also could be enhanced by the interactions of mucin/lactoferrin with α-amylase.

ROS-responsive drug-releasing injectable microgels for ameliorating myocardial infarction.

Despite of the recent advances in regulatory T cell (Treg) therapy, a limited number of available cells and specificity at the desired tissue site have severely compromised their efficacy. Herein, an injectable drug-releasing (MTK-TK-drug) microgel system in response to in situ stimulation by reactive oxygen species (ROS) was constructed with a coaxial capillary microfluidic system and UV curing. The spherical microgels with a size of 150 µm were obtained. The MTK-TK-drug microgels efficiently converted the pro-inflammatory Th17 cells into anti-inflammatory regulatory T cells (Treg) cells in vitro, and the ROS-scavenging materials synergistically enhanced the effect by modulating the inflammation microenvironment. Thus, the microgels significantly reduced cardiomyocyte apoptosis and decreased the inflammatory response in the early stages of post-myocardial infarction (MI) in vivo, thereby reducing fibrosis, promoting vascularization, and preserving cardiac function. Overall, our results indicate that the MTK-TK-drug microgels can attenuate the inflammatory response and improve MI therapeutic effects in vivo.

Epicardial transplantation of antioxidant polyurethane scaffold based human amniotic epithelial stem cell patch for myocardial infarction treatment.

Myocardial infarction (MI) is a leading cause of death globally. Stem cell therapy is considered a potential strategy for MI treatment. Transplantation of classic stem cells including embryonic, induced pluripotent and cardiac stem cells exhibited certain repairing effect on MI via supplementing cardiomyocytes, however, their clinical applications were blocked by problems of cell survival, differentiation, functional activity and also biosafety and ethical concerns. Here, we introduced human amniotic epithelial stem cells (hAESCs) featured with immunomodulatory activities, immune-privilege and biosafety, for constructing a stem cell cardiac patch based on porous antioxidant polyurethane (PUR), which demonstrated decent hAESCs compatibility. In rats, the administration of PUR-hAESC patch significantly reduced fibrosis and facilitated vascularization in myocardium after MI and consequently improved cardiac remodeling and function. Mechanistically, the patch provides a beneficial microenvironment for cardiac repair by facilitating a desirable immune response, paracrine modulation and limited oxidative milieu. Our findings may provide a potential therapeutic strategy for MI.

Shape-recovery of implanted shape-memory devices remotely triggered via image-guided ultrasound heating.

Shape-memory materials hold great potential to impart medical devices with functionalities useful during implantation, locomotion, drug delivery, and removal. However, their clinical translation is limited by a lack of non-invasive and precise methods to trigger and control the shape recovery, especially for devices implanted in deep tissues. In this study, the application of image-guided high-intensity focused ultrasound (HIFU) heating is tested. Magnetic resonance-guided HIFU triggered shape-recovery of a device made of polyurethane urea while monitoring its temperature by magnetic resonance thermometry. Deformation of the polyurethane urea in a live canine bladder (5 cm deep) is achieved with 8 seconds of ultrasound-guided HIFU with millimeter resolution energy focus. Tissue sections show no hyperthermic tissue injury. A conceptual application in ureteral stent shape-recovery reduces removal resistance. In conclusion, image-guided HIFU demonstrates deep energy penetration, safety and speed.

Control over the gradient differentiation of rat BMSCs on a PCL membrane with surface-immobilized alendronate gradient.

Gradient biomaterials can offer progressively changing signals to specific tissue interface, and thereby modulate the conjunction between different tissues. A linear density gradient of alendronate (Aln), a molecule that is capable of promoting osteogenic differentiation of bone mesenchymal stem cells (BMSCs), was created on an aminolyzed poly(ε-caprolactone) (PCL) membrane. X-ray photoelectron spectroscopy and quartz crystal microbalance with dissipation revealed the linear increase of the Aln amount as a function of the position on the PCL membrane. By contrast, the surface wettability and energy were kept unchanged. The surface-grafted Aln showed a stronger ability to induce the osteogenic differentiation of rat BMSCs than its counterpart in culture medium of the same amount, and the osteo-inductive culture medium. On the Aln-grafted gradient surface, the BMSCs showed gradient osteogenic differentiation as a function of membrane position in terms of cell morphology, alkaline phosphatase activity, calcium deposition, and the expression of osteogenesis marker proteins including collagen type I (COL I), Runt-related transcription factor 2 (Runx2), and osteocalcin (OCN).

In vivo self-assembled shape-memory polyurethane for minimally invasive delivery and therapy.

Advanced elastomers are highly in demand for the fabrication of medical devices for minimally invasive surgery (MIS). Herein, a shape memory and self-healing polyurethane (PCLUSe) composed of semi-crystalline poly(ε-caprolactone) (PCL) segments and interchangeable and antioxidative diselenide bonds was designed and synthesized. The excellent shape memory of PCLUSe contributed to the smooth MIS operation, leading to less surgical wounds than in the case of sternotomy. The diselenide bonds of PCLUSe contributed to the rapid self-healing under 405 nm irradiation within 60 s, and the alleviation of tissue oxidation post injury. After being delivered through a 10 mm diameter trocar onto a beating canine heart by MIS, two shape-recovered PCLUSe films self-assembled (self-healing) into a larger single patch (20 × 10 × 0.2 mm3) under the trigger of laser irradiation in situ, which could efficiently overcome the limited-size problem within MIS and meet a larger treatment area. The diselenide bonds in the PCLUSe cardiac patches protected the myocardium under oxidative stress post myocardial infarction (MI), and significantly maintained the cardiac functions.

[Experimental study on effect of Salvia miltiorrhiza on alveolar bone metabolism and variation in bone mass in diabetic rats].

OBJECTIVE: To study the effect of Salvia miltiorrhiza on alveolar bone metabolism and variation in bone mass in diabetic rats, in order to detect whether it has an inhibitory effect on alveolar bone osteoporosis caused by diabetics. METHOD: Intraperitoneal injection of alloxan induced diabetes in rats. After one week of observation and maintenance of stable blood sugar level, they were treated with S. miltiorrhiza. The rats were sacrificed at the eighth week after fasting for 12 h and blood samples were collected for analysis of blood glucose and rate of bone metabolism. Meanwhile, their alveolar bones were collected for determining bone mineral density (BMD) and histological sections were made for histomorphology observation. RESULT: Diabetic rats showed varying degrees of abnormality in bone metabolism indicators and significant reduction in bone mineral density. After treatment with S. miltiorrhiza, their symptoms reduced to some extend and all indicators were improved especially bone density. CONCLUSION: S. miltiorrhiza has a certain inhibitory effect on alveolar bone osteoporosis in diabetic rats in early stage.

Alleviating Oxidative Injury of Myocardial Infarction by a Fibrous Polyurethane Patch with Condensed ROS-Scavenging Backbone Units.

Excessive reactive oxygen species (ROS) generated after myocardial infarction (MI) result in the oxidative injury in myocardium. Implantation of antioxidant biomaterials, without the use of any type of drugs, is very appealing for clinical translation, leading to the great demand of novel biomaterials with high efficiency of ROS elimination. In this study, a segmented polyurethane (PFTU) with a high density of ROS-scavenging backbone units is synthesized by the reaction of poly(thioketal) dithiol (PTK) and poly(propylene fumarate) diol (PPF) (soft segments), thioketal diamine (chain extender), and 1,6-hexamethylene diisocyanate (HDI). Its chemical structure is verified by gel permeation chromatography (GPC), 1 H nuclear magnetic resonance (1 H NMR) spectroscopy, and Fourier transform infrared (FTIR) spectroscopy. The electrospun composite PFTU/gelatin (PFTU/Gt) fibrous patches show good antioxidation capacity and ROS-responsive degradation in vitro. Implantation of the PFTU/gelatin patches on the heart tissue surface in MI rats consistently decreases the ROS level, membrane peroxidation, and cell apoptosis at the earlier stage, which are not observed in the non-ROS-responsive polyurethane patch. Inflammation and fibrosis are also reduced in the PFTU/gelatin-treated hearts, resulting in the reduced left ventricular remodeling and better cardiac functions postimplantation for 28 d.

Multifunctional elastomer cardiac patches for preventing left ventricle remodeling after myocardial infarction in vivo.

Myocardial infarction (MI) is still a major cause of mortality and morbidity worldwide. Elastomer cardiac patches have shown great potential in preventing left ventricle (LV) remodeling post-MI by providing mechanical support to the infarcted myocardium. Improved therapeutic outcomes are expected by mediating pathological processes in the necrosis phase, inflammation phase, and fibrosis phase, through orchestrated biological and mechanical treatments. In this study, a mechanically robust multifunctional cardiac patch integrating reactive oxygen species (ROS)-scavenging, anti-inflammatory, and pro-angiogenic capabilities was developed to realize the integrative strategy. An elastomeric polyurethane (PFTU) containing ROS-sensitive poly (thioketal) (PTK) and unsaturated poly (propylene fumarate) (PPF) segments was synthesized, which was further clicked with pro-angiogenic Arg-Glu-Asp-Val (REDV) peptides to obtain PFTU-g-REDV (PR), and was formulated into a macroporous patch containing rosuvastatin (PRR). The mechanical support and multifunctional effects of the patch were confirmed in a rat MI model in vivo compared to the patches with only mechanical support, leading to reduced cell apoptosis, suppressed local inflammatory response, alleviated fibrosis, and induced angiogenesis. The cardiac functions and LV morphology were also well maintained. These results demonstrate the advantages of the integrated and orchestrated treatment strategy in MI therapy.

Scalable Milk-Derived Whey Protein Hydrogel as an Implantable Biomaterial.

There are limited naturally derived protein biomaterials for the available medical implants. High cost, low yield, and batch-to-batch inconsistency, as well as intrinsically differing bioactivity in some of the proteins, make them less beneficial as common implant materials compared to their synthetic counterparts. Here, we present a milk-derived whey protein isolate (WPI) as a new kind of natural protein-based biomaterial for medical implants. The WPI was methacrylated at 100 g bench scale, >95% conversion, and 90% yield to generate a photo-cross-linkable material. WPI-MA was further processed into injectable hydrogels, monodispersed microspheres, and patterned scaffolds with photo-cross-linking-based advanced processing methods including microfluidics and 3D printing. In vivo evaluation of the WPI-MA hydrogels showed promising biocompatibility and degradability. Intramyocardial implantation of injectable WPI-MA hydrogels in a model of myocardial infarction attenuated the pathological changes in the left ventricle. Our results indicate a possible therapeutic value of WPI-based biomaterials and give rise to a potential collaboration between the dairy industry and the production of medical therapeutics.

Poly(lactide-co-glycolide)/hydroxyapatite nanofibrous scaffolds fabricated by electrospinning for bone tissue engineering.

Poly(lactide-co-glycolide) (PLGA) nanofibrous composite scaffolds having nano-hydroxyapatite particles (HAp) in the fibers were prepared by electrospinning of PLGA and HAp with an average diameter of 266.6 ± 7.3 nm. Microscopy and spectroscopy characterizations confirmed integration of the crystalline HAp in the scaffolds. Agglomerates gradually appeared and increased on the fiber surface along with increase of the HAp concentration. In vitro mineralization in a 5 × simulated body fluid (SBF) revealed that the PLGA/HAp nanofibrous scaffolds had a stronger biomineralization ability than the control PLGA scaffolds. Biological performance of the nanofibrous scaffolds of the control PLGA and PLGA with 5 wt% HAp (PLGA/5HAp) was assessed by in vitro culture of neonatal mouse calvaria-derived MC3T3-E1 osteoblasts. Both types of the scaffolds could support cell proliferation and showed sharp increase of viability until 7 days, but the cells cultured on the PLGA/5HAp nanofibers showed a more spreading morphology. Despite the similar level of the cell viability and cell number at each time interval, the alkaline phosphatase secretion was significantly enhanced on the PLGA/5HAp scaffolds, indicating the higher bioactivity of the as-prepared nano-HAp and the success of the present method for preparing biomimetic scaffold for bone regeneration.

Conjugation of oxaliplatin with PEGylated-nanobody for enhancing tumor targeting and prolonging circulation.

Oxaliplatin is a platinum-based drug used in clinic for cancer chemotherapy. Despite of its success, the non-selective effect on normal cells causes severe side-effects and hampers its applications. Targeted delivery of oxaliplatin to cancer cells is an effective approach to enhance drug efficacy and reduce adverse effect. In this work, the Pt(IV) prodrug of oxaliplatin has been conjugated to poly(ethylene glycol) (PEG) modified nanobody in order to achieve tumor targeting as well as improved circulation in vivo. The Pt(IV) prodrug was site-specifically linked to an anti-epidermal growth factor receptor (EGFR) nanobody, so that the drug can be accumulated more pronounced in EGFR positive tumor cells than in normal cells. The effect of different length of PEG on the drug circulation has been investigated, while the fusion of anti-albumin nanobody was used for comparison. The result demonstrates that the prolonged drug circulation significantly increases the in vivo drug efficiency of the oxaliplatin-nanobody conjugate.

A cell-free ROS-responsive hydrogel/oriented poly(lactide-co-glycolide) hybrid scaffold for reducing inflammation and restoring full-thickness cartilage defectsin vivo.

The modulation of inflammation in tissue microenvironment takes an important role in cartilage repair and regeneration. In this study, a novel hybrid scaffold was designed and fabricated by filling a reactive oxygen species (ROS)-scavenging hydrogel (RS Gel) into a radially oriented poly(lactide-co-glycolide) (PLGA) scaffold. The radially oriented PLGA scaffolds were fabricated through a temperature gradient-guided phase separation and freeze-drying method. The RS Gel was formed by crosslinking the mixture of ROS-responsive hyperbranched polymers and biocompatible methacrylated hyaluronic acid (HA-MA). The hybrid scaffolds exhibited a proper compressive modulus, good ROS-scavenging capability, and cell compatibility.In vivotests showed that the hybrid scaffolds significantly regulated inflammation and promoted regeneration of hyaline cartilage after they were implanted into full-thickness cartilage defects in rabbits for 12 w. In comparison with the PLGA scaffolds, the neo-cartilage in the hybrid scaffolds group possessed more deposition of glycosaminoglycans and collagen type II, and were well integrated with the surrounding tissue.

A Dual Functional Nanoreactor for Synergistic Starvation and Photodynamic Therapy.

The combination of photodynamic therapy (PDT) and enzyme therapy is a highly desirable approach in malignant tumor therapies as it takes advantage of the spatial-controlled PDT and the effective enzyme-catalyzed bioreactions. However, it is a challenge to co-encapsulate hydrophilic enzymes and hydrophobic photosensitizers, and these two agents often interfere with each other. In this work, a protocell-like nanoreactor (GOx-MSN@MnPc-LP) has been designed for synergistic starvation therapy and PDT. In this nanoreactor, the hydrophilic glucose oxidase (GOx) is loaded in the pore of mesoporous silica nanoparticles (MSNs), while the hydrophobic manganese phthaleincyanide (MnPc) is loaded in the membrane layer of liposome. This spatial separation of two payloads protects GOx and MnPc from the cellular environment and avoids interference with each other. GOx catalyzes the oxidation of glucose, which generates hydrogen peroxide and gluconic acid, leading to the starvation therapy via glucose consumption in cancer cells, as well as the disruption of cellular redox balance. MnPc produces cytotoxic singlet oxygen under 730 nm laser irradiation, achieving PDT. The antitumor effects of the nanoreactor have been verified on tumor cells and tumor-bearing mice models. GOx-MSN@MnPc-LP efficiently inhibits tumor growth in vivo with a single treatment, indicating the robust synergy of starvation therapy and PDT treatment. This work also offers a versatile strategy for delivering hydrophilic enzymes and hydrophobic photosensitizers using a protocell-like nanoreactor for effective cancer treatment.