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Summary Tumor-associated adipocytes promote tumor growth by providing energy and causing chronic inflammation. Here, we have exploited the lipid metabolism to engineer adipocytes that serve as a depot to deliver cancer therapeutics at the tumor site. Rumenic acid (RA), as an anticancer fatty acid, and a doxorubicin prodrug (pDox) with a reactive oxygen species (ROS)-cleavable linker, are encapsulated in adipocytes to deliver therapeutics in a tumor-specific bioresponsive manner. After intratumoral or postsurgical administration, lipolysis releases the RA and pDox that is activated by intracellular ROS-responsive conversion, subsequently promoting antitumor efficacy. Furthermore, downregulation of PD-L1 expression is observed in tumor cells, favoring the emergence of CD4+ and CD8+ T cell-mediated immune responses.

Cancer immunotherapy aims to utilize the host immune system to kill cancer cells. Recent representative immunotherapies include T-cell transfer therapies, such as chimeric antigen receptor T cell therapy, antibody-based immunomodulator therapies, such as immune checkpoint blockade therapy, and cytokine therapies. Recently developed therapies leveraging engineered cells for immunotherapy against cancers have been reported to enhance antitumor efficacy while reducing side effects. Such therapies range from biologically, chemically and physically -engineered cells to bioinspired and biomimetic nanomedicines. In this review, advances of engineering cells for cancer immunotherapy are summarized, and prospects of this field are discussed.

Controlling postprandial glucose levels for diabetic patients is critical to achieve the tight glycemic control that decreases the risk for developing long-term micro- and macrovascular complications. Herein, we report a glucose-responsive oral insulin delivery system based on Fc receptor (FcRn)-targeted liposomes with glucose-sensitive hyaluronic acid (HA) shell for postprandial glycemic regulation. After oral administration, the HA shell can quickly detach in the presence of increasing intestinal glucose concentration due to the competitive binding of glucose with the phenylboronic acid groups conjugated with HA. The exposed Fc groups on the surface of liposomes then facilitate enhanced intestinal absorption in an FcRn-mediated transport pathway. In vivo studies on chemically-induced type 1 diabetic mice show this oral glucose-responsive delivery approach can effectively reduce postprandial blood glucose excursions. This work is the first demonstration of an oral insulin delivery system directly triggered by increasing postprandial glucose concentrations in the intestine to provide an on-demand insulin release with ease of administration.

Although therapies of cancer are advancing, it remains challenging for therapeutics to reach the sites of metastasis, which accounts for majority of cancer associated death. In this study, we have developed a strategy that guides an anti-programmed cell death-ligand 1 (aPDL1) antibody to accumulate in metastatic lesions to promote anti-tumour immune responses. Briefly, we have developed a combination in which Vadimezan disrupts tumour blood vessels of tumour metastases and facilitates the recruitment and activation of adoptively transferred aPDL1-conjugated platelets. In situ activated platelets generate aPDL1-decorated platelet-derived microparticles (PMP) that diffuse within the tumour and elicit immune responses. The proposed combination increases 10-fold aPDL1 antibody accumulation in lung metastases as compared to the intravenous administration of the antibody and enhances the magnitude of immune responses leading to improved antitumour effects., Cancer metastasis is the leading cause of death in patients, here, the authors show disrupting tumor vasculature could recruit and activate anti-PD-L1 engineered platelet at metastatic tumor sites to block the PD-1/PD-L1 crosstalk and enhance the anticancer immunotherapy.

Insulin therapy is the central component of treatment for type 1 and advanced type 2 diabetes; however, its narrow therapeutic window is associated with a risk of severe hypoglycemia. A glucose-responsive carrier that demonstrates consistent and slow basal insulin release under a normoglycemic condition and accelerated insulin release in response to hyperglycemia in real-time could offer effective blood glucose regulation with reduced risk of hypoglycemia. Here, we describe a poly(l-lysine)-derived biodegradable glucose-responsive cationic polymer for constructing polymer-insulin complexes for glucose-stimulated insulin delivery. The effects of the modification degree of arylboronic acid in the synthesized cationic polymer and polymer-to-insulin ratio on the glucose-dependent equilibrated free insulin level and the associated insulin release kinetics have been studied. In addition, the blood glucose regulation ability of these complexes and the associated glucose challenge-triggered insulin release are evaluated in type 1 diabetic mice.

Significance The efficacy of current diabetes treatments designed to reverse insulin deficiency is often limited by the frequent occurrence of acute hypoglycemia. To this end, a hybrid glucose-responsive delivery patch is engineered to function as a synthetic artificial pancreas by delivering insulin and glucagon upon hyperglycemic and hypoglycemic conditions, respectively. A mask-mediated polymerization method is developed to accommodate the insulin and glucagon modules that share a copolymerized matrix but comprise different ratios of the key monomers. The synergistic counterregulation of the two modules is found to enhance the capability of the hybrid patch in maintaining normoglycemia during plasma glucose fluctuation. This platform strategy could facilitate the development of customized therapeutic patches for closed-loop delivery in a precise manner.

BACKGROUND This study aimed to evaluate the prescription patterns and safety profiles of oral nonsteroidal anti-inflammatory drugs (NSAIDs) in three Chinese hospitals. METHODS The study analyzed the data of 50,732 patients who were prescribed oral NSAIDs from July 1, 2012 to August 31, 2019. The characteristics of these patients, the prescription patterns of NSAIDs, and the drug-related safety profiles were evaluated. RESULTS Oral NSAIDs were prescribed to patients of all ages. Of the patients, 81.88% were prescribed NSAIDs on only one occasion, and 91.64% were prescribed one type of NSAID only. The combination of different NSAIDs accounted for 2,360 person-times. Orthopedic departments most commonly used selective cyclo-oxygenase-2 (COX-2) inhibitors, while emergency departments most commonly used traditional NSAIDs. The incidences of gastrointestinal (GI) complications, cardiovascular (CV) events, and newonset hypertension were lower in patients treated with selective COX-2 inhibitors than those treated with traditional NSAIDs and NSAID combinations (P

Glucose-responsive insulin delivery systems that mimic pancreatic endocrine function could enhance health and improve quality of life for people with type 1 and type 2 diabetes with reduced β-cell function. However, insulin delivery systems with rapid in vivo glucose-responsive behaviour typically have limited insulin-loading capacities and cannot be manufactured easily. Here, we show that a single removable transdermal patch, bearing microneedles loaded with insulin and a non-degradable glucose-responsive polymeric matrix, and fabricated via in situ photopolymerization, regulated blood glucose in insulin-deficient diabetic mice and minipigs (for minipigs >25 kg, glucose regulation lasted >20 h with patches of ~5 cm2). Under hyperglycaemic conditions, phenylboronic acid units within the polymeric matrix reversibly form glucose–boronate complexes that—owing to their increased negative charge—induce the swelling of the polymeric matrix and weaken the electrostatic interactions between the negatively charged insulin and polymers, promoting the rapid release of insulin. This proof-of-concept demonstration may aid the development of other translational stimuli-responsive microneedle patches for drug delivery. A single removable transdermal patch bearing microneedles loaded with insulin and a non-degradable glucose-responsive polymeric matrix regulates blood glucose in insulin-deficient diabetic mice and minipigs.

Fluorescence is routinely used for in vivo tracking and imaging of molecules and nanostructures with assuming that the fluorescence intensity is proportional to the dye concentration. Herein, we report the unique tumor-specific fluorescence character of rhodamine B isothiocyanate derivatives (RBITCs), which emits fluorescence selectively in cancerous tissues, including small metastatic tumors, but is quenched in blood and healthy tissues. A preliminary mechanism study shows that binding of the thiourea group in the RBITCs on hemoglobin quenches their fluorescence, but the oxidation of the thiourea by the elevated reactive oxygen species in tumor activates the fluorescence. Thus, the fluorescent intensity of RBITCs is associated with the microenvironment of tissues and positively correlates with the cancer stages. These findings suggest that the RBITCs are not suitable for tracking of cargos in the presence of red blood cells but may be useful for cancer imaging and early diagnosis, and probing the tumor microenvironment.

MiR-133b is considered to be lowly expressed in osteoporosis patients. This study aimed to probe the role and in-depth mechanism of miR-133b in modulating osteoblast biological behavior and differentiation. The differential expressions of miR-133b and GNB4 in patients with osteoporosis and healthy control were analyzed based on the GEO database. Osteoblastic differentiation of hFOB 1.19 cells was induced in the culture medium containing 10 mM β-glycerophosphate, 50 nm dexamethasone, and 100 μg/ml ascorbic acid. The level of GNB4 was detected using quantitative real-time PCR (qRT-PCR) and Western blot. Cell viability and apoptosis were measured by Cell Counting Kit-8 (CCK-8) and flow cytometry assays, respectively. Western blot was also utilized to measure the levels of osteoblast-related proteins, including ALP, Runx2, Osterix, and OPN. GNB4 was identified and confirmed as a downstream target gene of miR-133b. The expression of miR-133b was declined while the expression of GNB4 was increased in osteoporosis patients. Importantly, up-regulation of miR-133b caused the increase of cell viability and the decrease of apoptosis, which could be blocked by overexpression of GNB4. Also, up-regulation of miR-133b promoted osteoblasts differentiation, as shown by the increase in the expression of ALP, Runx2, Osterix, and OPN. Similarly, this promoting impact resulted from miR-133b overexpression can be reversed via up-regulation of GNB4. These findings revealed that miR-133b can promote the viability and differentiation of osteoblasts by targeting GNB4, hoping to lay a feasible theoretical foundation for the clinical treatment of osteoporosis.

Effective anticancer nanomedicines need to exhibit prolonged circulation in blood, to extravasate and accumulate in tumours, and to be taken up by tumour cells. These contrasting criteria for persistent circulation and cell-membrane affinity have often led to complex nanoparticle designs with hampered clinical translatability. Here, we show that conjugates of small-molecule anticancer drugs with the polyzwitterion poly(2-(N-oxide-N,N-diethylamino)ethyl methacrylate) have long blood-circulation half-lives and bind reversibly to cell membranes, owing to the negligible interaction of the polyzwitterion with proteins and its weak interaction with phospholipids. Adsorption of the polyzwitterion-drug conjugates to tumour endothelial cells and then to cancer cells favoured their transcytosis-mediated extravasation into tumour interstitium and infiltration into tumours, and led to the eradication of large tumours and patient-derived tumour xenografts in mice. The simplicity and potency of the polyzwitterion-drug conjugates should facilitate the design of translational anticancer nanomedicines.

Indocyanine green (ICG), a safe and clinically approved near-infrared (NIR) dye, was recently explored as a potential photosensitizer due to its excellent photophysical properties. However, ICG tends to form aggregations in physiological solution, causing fluorescence quenching, fast blood clearance and thereby inefficient tumor accumulation. Herein, we report ICG-based nanodrug delivery systems formed by self-assembly of ICG and chemotherapeutic drugs without any excipients for combined chemo- and photo-therapy. Taking advantage of the amphiphilic aromatic structure, ICG readily bounded with hydrophobic aromatic drugs such as SN38 and formed well-dispersible nanoparticles, which reduced its aggregation-induced quenching and thus greatly improved its photodynamic efficiency. The loaded hydrophobic drugs elicited chemotherapy synergizing the photodynamic therapy, giving rise to much enhanced antitumor activity in vitro and in vivo against human glioblastoma cells and breast cancer cells upon NIR irradiation. The work demonstrates the fabrication of readily translational nanoformulations of hydrophobic drugs using amphiphilic drugs.

Individuals with type 1 and advanced type 2 diabetes require daily insulin therapy to maintain blood glucose levels in normoglycemic ranges to prevent associated morbidity and mortality. Optimal insulin delivery should offer both precise dosing in response to real-time blood glucose levels as well as a feasible and low-burden administration route to promote long-term adherence. A series of glucose-responsive insulin delivery mechanisms and devices have been reported to increase patient compliance while mitigating the risk of hypoglycemia. This review discusses currently available insulin delivery devices, overviews recent developments towards the generation of glucose-responsive delivery systems, and provides commentary on the opportunities and barriers ahead regarding the integration and translation of current glucose-responsive insulin delivery designs.

Radical surgery still represents the treatment choice for several malignancies. However, local and distant tumor relapses remain the major causes of treatment failure, indicating that a postsurgery consolidation treatment is necessary. Immunotherapy with checkpoint inhibitors has elicited impressive clinical responses in several types of human malignancies and may represent the ideal consolidation treatment after surgery. Here, we genetically engineered platelets from megakaryocyte (MK) progenitor cells to express the programmed cell death protein 1 (PD-1). The PD-1 platelet and its derived microparticle could accumulate within the tumor surgical wound and revert exhausted CD8+ T cells, leading to the eradication of residual tumor cells. Furthermore, when a low dose of cyclophosphamide (CP) was loaded into PD-1-expressing platelets to deplete regulatory T cells (Tregs), an increased frequency of reinvigorated CD8+ lymphocyte cells was observed within the postsurgery tumor microenvironment, directly preventing tumor relapse.

Generating artificial pancreatic beta cells by using synthetic materials to mimic glucose-responsive insulin secretion in a robust manner holds promise for improving clinical outcomes in people with diabetes. Here, we describe the construction of artificial beta cells (AβCs) with a multicompartmental 'vesicles-in-vesicle' superstructure equipped with a glucose-metabolism system and membrane-fusion machinery. Through a sequential cascade of glucose uptake, enzymatic oxidation and proton efflux, the AβCs can effectively distinguish between high and normal glucose levels. Under hyperglycemic conditions, high glucose uptake and oxidation generate a low pH (

Obesity is one of the most serious public health problems in the 21st century that may lead to many comorbidities such as type-2 diabetes, cardiovascular diseases, and cancer. Current treatments toward obesity including diet, physical exercise, pharmacological therapy, as well as surgeries are always associated with low effectiveness or undesired systematical side effects. In order to enhance treatment efficiency with minimized side effects, we developed a transcutaneous browning agent patch to locally induce adipose tissue transformation. This microneedle-based patch can effectively deliver browning agents to the subcutaneous adipocytes in a sustained manner and switch on the “browning” at the targeted region. It is demonstrated that this patch reduces treated fat pad size, increases whole body energy expenditure, and improves type-2 diabetes in vivo in a diet-induced obesity mouse model.

Reactive oxygen species (ROS) plays a key role in therapeutic effects as well as side effects of platinum drugs. Cisplatin mediates activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX), which triggers oxygen (O2) to superoxide radical (O2•–) and its downstream H2O2. Through the Fenton’s reaction, H2O2 could be catalyzed by Fe2+/Fe3+ to the toxic hydroxyl radicals (•OH), which cause oxidative damages to lipids, proteins, and DNA. By taking the full advantage of Fenton’s chemistry, we herein demonstrated tumor site-specific conversion of ROS generation induced by released cisplatin and Fe2+/Fe3+ from iron-oxide nanocarriers with cisplatin(IV) prodrugs for enhanced anticancer activity but minimized systemic toxicity.

Insulin administration for management of diabetes is accompanied by hypoglycemia, which is expected to be mitigated by glucose-responsive smart insulin that has self-regulation ability in response to blood glucose level (BGL) fluctuation. Here, we have prepared a new insulin analog by modifying insulin with forskolin (designated as insulin-F), a glucose-transporter (Glut) inhibitor. In vitro, insulin-F is capable of binding to Glut on erythrocyte ghosts, which can be inhibited by glucose and cytochalasin B. Upon subcutaneous injection in type 1 diabetic mice, insulin-F maintains the BGLs below 200 mg/mL for up to 10 hours, and achieves 20 hours with two sequential injections. Meanwhile, insulin-F also binds to endogenous Gluts. Upon a glucose challenge, the elevated level of glucose competitively replaces and liberates insulin-F that binds to Glut, restoring BGLs to the normal range rapidly.

People with type 1 or advanced type 2 diabetes are highly dependent on insulin. However, insulin cannot match its function to daily varying blood glucose levels, putting people with diabetes at risk of hypoglycemia. Glucose-responsive insulin is capable of improving blood glucose manipulation and elevating the life quality of people with diabetes. Therefore, enormous endeavors have been devoted to developing glucose-responsive insulin formulations, including glucose-responsive insulin delivery systems and glucose-responsive insulin analogs. In this review, we focus on glucose-responsive insulin analogs, especially three representatives, including phenylboronic acid-mediated, glucose transporter-mediated and lectin-mediated glucose-responsive insulin analogs. Based on the published studies, the opportunities and challenges to engineering glucose-responsive insulin analogs are also discussed. Keywords: Diabetes, Insulin, Glucose-responsive, Drug delivery, Drug discovery

Despite the promising efficacy of immune checkpoint blockade (ICB) in treating many types of cancers, the clinical benefits have often been restricted by the low objective response rates and systemic immune-related adverse events. Here, a bioresponsive ICB treatment is developed based on the reactive oxygen species (ROS)-sensitive protein complex for controlled sequential release of anti- "don't eat me" signal antibody (aCD47) and antiprogrammed cell death protein 1 (aPD1), by leveraging the abundant ROS in the tumor microenvironment (TME). These protein complexes can also act as scavengers of ROS in the TME to reverse the immunosuppressive responses, thereby enhancing antitumor efficacy in vivo. In a melanoma cancer model, the synergistic antitumor efficacy was achieved, which was accompanied by enhanced T cell immune responses together with reduced immunosuppressive responses.

Insulin therapy in the setting of type 1 and advanced type 2 diabetes is complicated by increased risk of hypoglycemia. This potentially fatal complication could be mitigated by a glucose-responsive insulin analog. We report an insulin-facilitated glucose transporter (Glut) inhibitor conjugate, in which the insulin molecule is rendered glucose-responsive via conjugation to an inhibitor of Glut. The binding affinity of this insulin analog to endogenous Glut is modulated by plasma and tissue glucose levels. In hyperglycemic conditions (e.g., uncontrolled diabetes or the postprandial state), the in situ-generated insulin analog-Glut complex is driven to dissociate, freeing the insulin analog and glucose-accessible Glut to restore normoglycemia. Upon overdose, enhanced binding of insulin analog to Glut suppresses the glucose transport activity of Glut to attenuate further uptake of glucose. We demonstrate the ability of this insulin conjugate to regulate blood glucose levels within a normal range while mitigating the risk of hypoglycemia in a type 1 diabetic mouse model.

Insulin therapy is necessary to regulate blood glucose levels for people with type 1 diabetes and commonly used in advanced type 2 diabetes. Although subcutaneous insulin administration via hypodermic injection or pump-mediated infusion is the standard route of insulin delivery, it may be associated with pain, needle phobia, and decreased adherence, as well as the risk of infection. Therefore, transdermal insulin delivery has been widely investigated as an attractive alternative to subcutaneous approaches for diabetes management in recent years. Transdermal systems designed to prevent insulin degradation and offer controlled, sustained release of insulin may be desirable for patients and lead to increased adherence and glycemic outcomes. A challenge for transdermal insulin delivery is the inefficient passive insulin absorption through the skin due to the large molecular weight of the protein drug. In this review, we focus on the different transdermal insulin delivery techniques and their respective advantages and limitations, including chemical enhancers-promoted, electrically enhanced, mechanical force-triggered, and microneedle-assisted methods.

Background Imrecoxib, a novel cyclooxygenase (COX-2) selective non-steroidal anti-inflammatory drug (NSAID), has been approved in China for more than 9 years. This study aimed to assess the efficacy and safety of imrecoxib compared with celecoxib for patients with moderate or severe acute pain following oral surgery. Methods Patients with moderate or severe pain within 6 hours following surgery were enrolled in this randomized, active-control trial. Patients were randomly assigned (1:1) to receive either imrecoxib or celecoxib. Pain assessments on the visual analog scale, verbal rating scale, and pain relief were conducted at 0.5, 1, 2, 4, 6, 9, 12, and 24 hours after the first dose. Adverse events were also recorded. Results Eighty-seven patients were approached from November 2018 to August 2019. Of these, 60 were eligible for randomization. Ultimately, 56 patients (imrecoxib group, n=27; celecoxib group, n=29) were included in the analysis. The difference in total pain relief (TOTPAR) between the imrecoxib and celecoxib groups was 1.03 [95% confidence interval (CI): -1.31-3.77], with the lower bound of the CI above the specified non-inferiority boundary. No perioperative complications were observed in the imrecoxib group during the 24-hour period after the first dose. Conclusions Imrecoxib could significantly relieve pain and has a non-inferior analgesic efficacy compared to celecoxib with good tolerance following oral surgery.

Blood glucose monitoring is a daily routine of people with type 1 or advanced type 2 diabetes. Efforts on minimizing invasiveness, improving portability, and enhancing sustainability of the existing glucose monitoring devices are demanding for elevating patient compliance. Here, we describe a minimally invasive colloidal crystal microneedle (MN) patch for naked-eye glucose monitoring. The glucose-responsive colloidal crystal (GCC)-MN is designed with a polymeric core to mechanically support a shell of GCC for glucose sensing and reporting. The GCC-MN patch could translate the glucose concentrations into naked-eye distinguishable color changes within 5 min, and such glucose responsiveness is reversible. Demonstrated in a type 1 diabetic mouse model, the interstitial fluid extraction, glucose sensing, and resulting glucose-relevant color display procedures are simultaneously achieved with this GCC-MN patch.

Nanoformulations have been extensively explored to deliver water-insoluble drugs, but they generally use exotic new materials, for instance, amphiphilic block copolymers, which must first go through extensively clinical trials and be approved as drug excipients before any clinical uses. We hypothesize that using clinical amphiphilic drugs as surfactants to self-assemble with and thus solubilize hydrophobic drugs will lead to readily translational nanoformulations as they contain no new excipients. Herein, we show the first example of such excipient-free nanodispersions using an amphiphilic anti-tumor drug, irinotecan hydrochloride (CPT11). CPT11 self-assembles with its insoluble active parent drug, 7-ethyl-10-hydroxy camptothecin (SN38), into stable and water-dispersible nanoparticles, increasing SN38's water solubility by thousands of times up to 25 mg/mL with a loading efficiency close to 100%. The versatility of this approach is also demonstrated by fabricating nanodispersions of CPT11 with other water-insoluble drugs including paclitaxel (PTX) and camptothecin (CPT). These nanodispersions have much increased bioavailability and thereby improved anti-cancer activities. Thus, this strategy, using clinically proven amphiphilic drugs as excipients to fabricate nanodispersions, avoids new materials and makes readily translational nanoformulations of hydrophobic drugs.

The pathogenesis of Type 1 diabetes (T1D) arises from the destruction of insulin-producing β-cells by islet-specific autoreactive T cells. Inhibition of islet-specific autoreactive T cells to rescue β-cells is a promising approach to treat new-onset T1D. The immune checkpoint signal axis programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) can effectively regulate the activity of T cells and prevent autoimmune attack. Here, megakaryocyte progenitor cells are genetically engineered to overexpress PD-L1 to produce immunosuppressive platelets. The PD-L1-overexpressing platelets (designated PD-L1 platelets) accumulate in the inflamed pancreas and may suppress the activity of pancreas autoreactive T cells in newly hyperglycemic non-obese diabetic (NOD) mice, protecting the insulin-producing β-cells from destruction. Moreover, PD-L1 platelet treatment also increases the percentage of the regulatory T cells (Tregs) and maintains immune tolerance in the pancreas. It is demonstrated that the rescue of β-cells by PD-L1 platelets can effectively maintain normoglycemia and reverse diabetes in newly hyperglycemic NOD mice.

A microneedle cardiac stromal cell patch has been developed for therapeutic heart regeneration after myocardial infarction., We engineered a microneedle patch integrated with cardiac stromal cells (MN-CSCs) for therapeutic heart regeneration after acute myocardial infarction (MI). To perform cell-based heart regeneration, cells are currently delivered to the heart via direct muscle injection, intravascular infusion, or transplantation of epicardial patches. The first two approaches suffer from poor cell retention, while epicardial patches integrate slowly with host myocardium. Here, we used polymeric MNs to create “channels” between host myocardium and therapeutic CSCs. These channels allow regenerative factors secreted by CSCs to be released into the injured myocardium to promote heart repair. In the rat MI model study, the application of the MN-CSC patch effectively augmented cardiac functions and enhanced angiomyogenesis. In the porcine MI model study, MN-CSC patch application was nontoxic and resulted in cardiac function protection. The MN system represents an innovative approach delivering therapeutic cells for heart regeneration.

Patients with acute myeloid leukaemia who relapse following therapy have few treatment options and face poor outcomes. Immune checkpoint inhibition, for example, by antibody-mediated programmed death-1 (PD-1) blockade, is a potent therapeutic modality that improves treatment outcomes in acute myeloid leukaemia. Here, we show that systemically delivered blood platelets decorated with anti-PD-1 antibodies (aPD-1) and conjugated to haematopoietic stem cells (HSCs) suppress the growth and recurrence of leukaemia in mice. Following intravenous injection into mice bearing leukaemia cells, the HSC–platelet–aPD-1 conjugate migrated to the bone marrow and locally released aPD-1, significantly enhancing anti-leukaemia immune responses, and increasing the number of active T cells, production of cytokines and chemokines, and survival time of the mice. This cellular conjugate also promoted resistance to re-challenge with leukaemia cells. Taking advantage of the homing capability of HSCs and in situ activation of platelets for the enhanced delivery of a checkpoint inhibitor, this cellular combination-mediated drug delivery strategy can significantly augment the therapeutic efficacy of checkpoint blockade. The systemic administration of haematopoietic stem cells conjugated to anti-PD-1-decorated platelets in leukaemic mice promotes the delivery of the checkpoint inhibitor to the bone marrow and suppresses the growth and recurrence of leukaemia.

Cancer recurrence after surgical resection remains a significant cause of treatment failure. Here, we have developed an in situ formed immunotherapeutic bioresponsive gel that controls both local tumour recurrence after surgery and development of distant tumours. Briefly, calcium carbonate nanoparticles pre-loaded with the anti-CD47 antibody are encapsulated in the fibrin gel and scavenge H+ in the surgical wound, allowing polarization of tumour-associated macrophages to the M1-like phenotype. The released anti-CD47 antibody blocks the ‘don’t eat me’ signal in cancer cells, thereby increasing phagocytosis of cancer cells by macrophages. Macrophages can promote effective antigen presentation and initiate T cell mediated immune responses that control tumour growth. Our findings indicate that the immunotherapeutic fibrin gel ‘awakens’ the host innate and adaptive immune systems to inhibit both local tumour recurrence post surgery and potential metastatic spread. A gel with therapeutic nanoformulation that can be sprayed at the tumour resection site after surgery activates immune response in the tissue microenviroment, inhibiting tumour recurrence and potential metastasis.

The porous structure of the natural bone not only has the characteristics of lightweight and high strength but also is conducive to the growth of cells and tissues due to interconnected pores. In this paper, a novel gradient-controlled parametric modeling technology is presented to design bone tissue engineering (BTE) scaffold. First of all, the method functionalizes the pore distribution in the bone tissue, and reconstructs the pore distribution of the bone tissue in combination with the pathological analysis of the bone defect area of the individual patient. Then, based on the reconstructed pore distribution, the Voronoi segmentation algorithm and the contour interface optimization method are used to reconstruct the whole model of the bone tissue. Finally, the mechanical properties of the scaffold are studied by the finite element analysis of different density gradient scaffolds. The results show that the method is highly feasible. BTE scaffold can be designed by irregular design methods and adjustment of pore distribution parameters, which is similar with natural bone in structural characteristics and biomechanical properties

Although cancer immunotherapy based on immune checkpoint inhibitors holds great promise toward many types of cancers, several challenges still remain, associated with low objective response of patient rate as well as systemic side effects. Here, a combination immunotherapy strategy is developed based on a thermogelling reactive oxygen species (ROS)-responsive polypeptide gel for sustained release of anti-programmed cell death-ligand 1 antibody and dextro-1-methyl tryptophan, inhibitor of indoleamine-2,3-dioxygenase with leveraging the ROS level in the tumor microenvironment. This bioresponsive gel depot can effectively reduce the local ROS level and facilitate release of immunotherapeutics, which leads to enhanced anti-melanoma efficacy in vivo.

A bioinspired glucose-responsive insulin delivery system for self-regulation of blood glucose levels is desirable for improving health and quality of life outcomes for patients with type 1 and advanced type 2 diabetes. Here we describe a painless core–shell microneedle array patch consisting of degradable cross-linked gel for smart insulin delivery with rapid responsiveness and excellent biocompatibility. This gel-based device can partially dissociate and subsequently release insulin when triggered by hydrogen peroxide (H2O2) generated during the oxidation of glucose by a glucose-specific enzyme covalently attached inside the gel. Importantly, the H2O2-responsive microneedles are coated with a thin-layer embedding H2O2-scavenging enzyme, thus mimicking the complementary function of enzymes in peroxisomes to protect normal tissues from injury caused by oxidative stress. Utilizing a chemically induced type 1 diabetic mouse model, we demonstrated that this smart insulin patch with a bioresponsive core and protective shell could effectively regulate the blood glucose levels within a normal range with improved biocompatibility.

A tumour microenvironment imposes barriers to the passive diffusion of molecules, which renders tumour penetration an unresolved obstacle to an effective anticancer drug delivery. Here, we present a γ-glutamyl transpeptidase-responsive camptothecin–polymer conjugate that actively infiltrates throughout the tumour tissue through transcytosis. When the conjugate passes on the luminal endothelial cells of the tumour blood vessels or extravasates into the tumour interstitium, the overexpressed γ-glutamyl transpeptidase on the cell membrane cleaves the γ-glutamyl moieties of the conjugate to generate positively charged primary amines. The resulting cationic conjugate undergoes caveolae-mediated endocytosis and transcytosis, which enables transendothelial and transcellular transport and a relatively uniform distribution throughout the tumour. The conjugate showed a potent antitumour activity in mouse models that led to the eradication of small solid tumours (~100 mm3) and regression of large established tumours with clinically relevant sizes (~500 mm3), and significantly extended the survival of orthotopic pancreatic tumour-bearing mice compared to that with the first-line chemotherapeutic drug gemcitabine. A zwitterionic camptothecin–polymer conjugate that is enzymatically transformed in a cationic molecule at the tumour periphery penetrates deep into tumours via caveolae-mediated endocytosis and transcytosis, resulting in high anticancer efficiency in vivo.

Self-regulating glucose-responsive insulin delivery systems have great potential to improve clinical outcomes and quality of life among patients with diabetes. Herein, an H2 O2 -labile and positively charged amphiphilic diblock copolymer is synthesized, which is subsequently used to form nano-sized complex micelles (NCs) with insulin and glucose oxidase of pH-tunable negative charges. Both NCs are loaded into the crosslinked core of a microneedle array patch for transcutaneous delivery. The microneedle core is additionally coated with a thin sheath structure embedding H2 O2 -scavenging enzyme to mitigate the injury of H2 O2 toward normal tissues. The resulting microneedle patch can release insulin with rapid responsiveness under hyperglycemic conditions owing to an oxidative and acidic environment because of glucose oxidation, and can therefore effectively regulate blood glucose levels within a normal range on a chemically induced type 1 diabetic mouse model with enhanced biocompatibility.

Objective: To find out the effects of domperidone in combination with omeprazole in the treatment of chronic superficial gastritis (CSG). Methods: Ninety-six patients who suffered from CSG and received treatment in the Binzhou People’s Hospital from July 2013 to July 2014 were selected as research subjects. They were divided into a control group (48 cases) and a test group (48 cases) using double blind method. Patients in the control group were treated by omeprazole, while patients in the observation group were treated by domperidone in combination with omeprazole. The clinical effects of the two groups were observed and analyzed. Results: The scores of symptoms had no significant difference between the two groups before treatment. The improvement of the scores of symptoms in the test group was superior to that in the control group after treatment (P

Patients with low-immunogenic tumors respond poorly to immune checkpoint blockade (ICB) targeting the programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway. Conversely, patients responding to ICB can experience various side effects. We have thus engineered a therapeutic scaffold that, when formed in situ, allows the local release of gemcitabine (GEM) and an anti-PD-L1 blocking antibody (aPDL1) with distinct release kinetics. The scaffold consists of reactive oxygen species (ROS)-degradable hydrogel that releases therapeutics in a programmed manner within the tumor microenvironment (TME), which contains abundant ROS. We found that the aPDL1-GEM scaffold elicits an immunogenic tumor phenotype and promotes an immune-mediated tumor regression in the tumor-bearing mice, with prevention of tumor recurrence after primary resection.

Type 1 and advanced type 2 diabetes treatment involves daily injections or continuous infusion of exogenous insulin aimed at regulating blood glucose levels in the normoglycemic range. However, current options for insulin therapy are limited by the risk of hypoglycemia and are associated with suboptimal glycemic control outcomes. Therefore, a range of glucose-responsive components that can undergo changes in conformation or show alterations in intermolecular binding capability in response to glucose stimulation has been studied for ultimate integration into closed-loop insulin delivery or "smart insulin" systems. Here, an overview of the evolution and recent progress in the development of molecular approaches for glucose-responsive insulin delivery systems, a rapidly growing subfield of precision medicine, is presented. Three central glucose-responsive moieties, including glucose oxidase, phenylboronic acid, and glucose-binding molecules are examined in detail. Future opportunities and challenges regarding translation are also discussed.

Patients with advanced melanoma that is of low tumor-associated antigen (TAA) expression often respond poorly to PD-1/PD-L1 blockade therapy. Epigenetic modulators, such as hypomethylation agents (HMAs), can enhance the antitumor immune response by inducing TAA expression. Here, a dual bioresponsive gel depot that can respond to the acidic pH and reactive oxygen species (ROS) within the tumor microenvironment (TME) for codelivery of anti-PD1 antibody (aPD1) and Zebularine (Zeb), an HMA, is engineered. aPD1 is first loaded into pH-sensitive calcium carbonate nanoparticles (CaCO3 NPs), which are then encapsulated in the ROS-responsive hydrogel together with Zeb (Zeb-aPD1-NPs-Gel). It is demonstrated that this combination therapy increases the immunogenicity of cancer cells, and also plays roles in reversing immunosuppressive TME, which contributes to inhibiting the tumor growth and prolonging the survival time of B16F10-melanoma-bearing mice.

A platelet membrane-coated biomimetic nanocarrier, which could sequentially target bone microenvironment and myeloma cells to enhance the drug availability at the myeloma site and decrease the off-target effects, was developed for inhibiting the multiple myeloma growth and simultaneously eradicating the thrombus complication.

Despite the promising efficacy of immunoregulation in cancer therapy, the clinical benefit has been restricted by inefficient infiltration of lymphocytes in the evolution of immune evasion. Also, immune-related adverse events have often occurred due to the off-target binding of therapeutics to normal tissues after systematic treatment. In light of this, we have developed a synergistic immunotherapy strategy that locally targets the immunoinhibitory receptor programmed cell death protein 1 (PD1) and immunosuppressive enzyme indoleamine 2,3-dioxygenase (IDO) for the treatment of melanoma through a microneedle-based transcutaneous delivery approach. The embedded immunotherapeutic nanocapsule loaded with anti-PD1 antibody (aPD1) is assembled from hyaluronic acid modified with 1-methyl-dl-tryptophan (1-MT), an inhibitor of IDO. This formulation method based on the combination strategy of "drug A in carriers formed by incorporation of drug B" facilitates the loading capacity of therapeutics. Moreover, the resulting delivery device elicits the sustained release and enhances retention of checkpoint inhibitors in the tumor microenvironment. Using a B16F10 mouse melanoma model, we demonstrate that this synergistic treatment has achieved potent antitumor efficacy, which is accompanied by enhanced effective T cell immunity as well as reduced immunosuppression in the local site.

Multiple preclinical evidences have supported the potential value of mesenchymal stem cells (MSCs) for treatment of acute lung injury (ALI). However, few studies focus on the dynamic tropism of MSCs in animals with acute lung injury. In this study, we track systemically transplanted human bone marrow-derived mesenchymal stem cells (hBMSCs) in NOD/SCID mice with smoke inhalation injury (SII) through bioluminescence imaging (BLI). The results showed that hBMSCs systemically delivered into healthy NOD/SCID mouse initially reside in the lungs and then partially translocate to the abdomen after 24 h. Compared with the uninjured control group treated with hBMSCs, higher numbers of hBMSCs were found in the lungs of the SII NOD/SCID mice. In both the uninjured and SII mice, the BLI signals in the lungs steadily decreased over time and disappeared by 5 days after treatment. hBMSCs significantly attenuated lung injury, elevated the levels of KGF, decreased the levels of TNF-αin BALF, and inhibited inflammatory cell infiltration in the mice with SII. In conclusion, our findings demonstrated that more systemically infused hBMSCs localized to the lungs in mice with SII. hBMSC xenografts repaired smoke inhalation-induced lung injury in mice. This repair was maybe due to the effect of anti-inflammatory and secreting KGF of hMSCs but not associated with the differentiation of the hBMSCs into alveolar epithelial cells.

A composition comprising a bioresponsive (e.g., reactive oxygen species (ROS)-responsive), antibiotic- and/or absorbent-loaded polymeric network is described. In some cases, the composition can release the antibiotic loaded therein in response to ROS or another stimulus related to inflammation. Microneedles, microneedle arrays, and skin patches comprising the composition are also described, as well as methods of treating acne or other inflammatory/infectious skin conditions.