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Biomaterials play an integral role in treatment of external auditory canal (EAC) diseases. Regarding the special anatomic structure and physiological characteristics of EAC, careful selection of applicable biomaterials was essential step towards effective management of EAC conditions. The bioactive materials can provide reasonable biocompatibility, reduce risk of host pro-inflammatory response and immune rejection, and promote the healing process. In therapeutic procedure, biomaterials were employed for covering or packing the wound, protection of the damaged tissue, and maintaining of normal structures and functions of the EAC. Therefore, understanding and application of biomaterials was key to obtaining great rehabilitation in therapy of EAC diseases. In clinical practice, biomaterials were recognized as an important part in the treatment of different EAC diseases. The choice of biomaterials was distinct according to the requirements of various diseases. As a result, awareness of property regarding different biomaterials was fundamental for appropriate selection of therapeutic substances in different EAC diseases. In this review, we firstly introduced the characteristics of EAC structures and physiology, and EAC pathologies were summarized secondarily. From the viewpoint of biomaterials, the different materials applied to individual diseases were outlined in categories. Besides, the underlying future of therapeutic EAC biomaterials was discussed.

Immunosuppression tumor microenvironment (TME) seriously impedes anti-tumor immune response, resulting in poor immunotherapy effect of cancer. This study develops a folate-modified delivery system to transport the plasmids encoding immune stimulatory chemokine CKb11 and PD-L1 inhibitors to tumor cells, resulting in high CKb11 secretion from tumor cells, successfully activating immune cells and increasing cytokine secretion to reshape the TME, and ultimately delaying tumor progression. The chemokine CKb11 enhances the effectiveness of tumor immunotherapy by increasing the infiltration of immune cells in TME. It can cause high expression of IFN-γ, which is a double-edged sword that inhibits tumor growth while causing an increase in the expression of PD-L1 on tumor cells. Therefore, combining CKb11 with PD-L1 inhibitors can counterbalance the suppressive impact of PD-L1 on anti-cancer defense, leading to a collaborative anti-tumor outcome. Thus, utilizing nanotechnology to achieve targeted delivery of immune stimulatory chemokines and immune checkpoint inhibitors to tumor sites, thereby reshaping immunosuppressive TME for cancer treatment, has great potential as an immunogene therapy in clinical applications.

Atherosclerosis is a significant contributor to global cardiovascular disease. Reducing the formation of atherosclerotic plaque effectively can lead to a decrease in cardiovascular diseases. Therefore, controlling macrophage function is crucial. This study presents the creation of a bifunctional nanoparticle that is specific to macrophages to achieve intracellular and extracellular synergistic therapy for restoring macrophage functions. The nanoparticle is conjugated with anti-CD47 antibody to modulate extracellular CD47-SIRPα phagocytic signaling axis on the outer surface of macrophages and encapsulates the NLRP3 inhibitor (CY-09) to regulate intracellular inflammation response of macrophages. The results showed that the nanoparticles accumulate in the atherosclerotic plaque, alter macrophage phagocytosis, inhibit NLRP3 inflammasome activation, and decrease the plaque burden in Apoe−/−mice whilst ensuring safety. Examination of single-cell RNA sequencing indicates that this multifunctional nanoparticle decreases the expression of genes linked to inflammation and manages inflammatory pathways in the plaque lesion. This study proposes a synergistic therapeutic approach that utilizes a bifunctional nanoparticle, conjugated with anti-CD47, to regulate the microenvironment of plaques.

Post-extraction alveolar bone atrophy greatly hinders the subsequent orthodontic tooth movement (OTM) or implant placement. In this study, we synthesized biodegradable bifunctional bioactive calcium phosphorus nanoflowers (NFs) loaded with abaloparatide (ABL), namely ABL@NFs, to achieve spatiotemporal management for alveolar bone regeneration. The NFs exhibited a porous hierarchical structure, high drug encapsulation efficacy, and desirable biocompatibility. ABL was initially released to recruit stem cells, followed by sustained release of Ca2+and PO43–for in situinterface mineralization, establishing an osteogenic “biomineralized environment”. ABL@NFs successfully restored morphologically and functionally active alveolar bone without affecting OTM. In conclusion, the ABL@NFs demonstrated promising outcomes for bone regeneration under orthodontic condition, which might provide a desirable reference of man-made “bone powder” in the hard tissue regeneration field.

Myocardial infarction (MI) causes irreversible damage to the heart muscle, seriously threatening the lives of patients. Injectable hydrogels have attracted extensive attention in the treatment of MI. By promoting the coupling of mechanical and electrical signals between cardiomyocytes, combined with synergistic therapeutic strategies targeting the pathological processes of inflammation, proliferation, and fibrotic remodeling after MI, it is expected to improve the therapeutic effect. In this study, a pH/ROS dual-responsive injectable hydrogel was developed by modifying xanthan gum and gelatin with reversible imine bond and boronic ester bond double crosslinking. By encapsulating polydopamine-rosmarinic acid nanoparticles to achieve on-demand drug release in response to the microenvironment of MI, thereby exerting anti-inflammatory, anti-apoptotic, and anti-fibrosis effects. By adding conductive composites to improve the conductivity and mechanical strength of the hydrogel, restore electrical signal transmission in the infarct area, promote synchronous contraction of cardiomyocytes, avoid induced arrhythmias, and induce angiogenesis. Furthermore, the multifunctional hydrogel promoted the expression of cardiac-specific markers to restore cardiac function after MI. The in vivo and in vitro results demonstrate the effectiveness of this synergistic comprehensive treatment strategy in MI treatment, showing great application potential to promote the repair of infarcted hearts.

Cartilage injury affects numerous individuals, but the efficient repair of damaged cartilage is still a problem in clinic. Hydrogel is a potent scaffold candidate for tissue regeneration, but it remains a big challenge to improve its mechanical property and figure out the interaction of chondrocytes and stiffness. Herein, a novel hybrid hydrogel with tunable stiffness was fabricated based on methacrylated gelatin (GelMA) and iron oxide nanoparticles (Fe2O3) through chemical bonding. The stiffness of Fe2O3/GelMA hybrid hydrogel was controlled by adjusting the concentration of magnetic nanoparticles. The hydrogel platform with tunable stiffness modulated its cellular properties including cell morphology, microfilaments and Young's modulus of chondrocytes. Interestingly, Fe2O3/GelMA hybrid hydrogel promoted oxidative phosphorylation of mitochondria and facilitated catabolism of lipids in chondrocytes. As a result, more ATP and metabolic materials generated for cellular physiological activities and organelle component replacements in hybrid hydrogel group compared to pure GelMA hydrogel. Furthermore, implantation of Fe2O3/GelMA hybrid hydrogel in the cartilage defect rat model verified its remodeling potential. This study provides a deep understanding of the bio-mechanism of Fe2O3/GelMA hybrid hydrogel interaction with chondrocytes and indicates the hydrogel platform for further application in tissue engineering.

Gastric cancer is the fifth most common cancer and the third leading cause of cancer death worldwide, posing a severe threat to human health. Surgical resection remains the most preferred option for gastric cancer treatment. However, for advanced gastric cancer, the curative effect of surgical resection is usually limited by the local recurrence, peritoneal carcinomatosis, or distal metastasis. Intraoperative chemotherapy is an attractive in situ adjuvant treatment strategy to reduce the recurrence and metastasis after surgical resection. Here, we designed a 5-fluorouracil (5-FU) and cis-platinum (DDP) co-delivery system based on a biodegradable temperature-sensitive hydrogel (PDLLA-PEG-PDLLA, PLEL) for intraoperative adjuvant combination chemotherapy of gastric cancer. This 5-FU + DDP/PLEL hydrogel system characterized by a special sol-gel phase transition in response to physiological temperature and presented sustained drug release in vitro and in vivo. A strong synergistic cell proliferation inhibition and apoptosis promotion of 5-FU + DDP/PLEL were observed against gastric cancer MKN45-luc cells. After intraperitoneal injection, the dual-drug loaded hydrogel formulation showed superior anti-tumor effects than the single-drug carrying hydrogels and combination of free 5-FU and DDP on the gastric cancer peritoneal carcinomatosis model. The use of hydrogel for dual-drug delivery had benefited to fewer side effects as well. What's more, we established a mouse model for postsurgical residual tumors and peritoneal carcinomatosis of gastric cancer, in which the intraoperative administration of 5-FU + DDP/PLEL also remarkably inhibited the local recurrence of the orthotopic tumors and the growth of the abdominal metastatic tumors, resulting in an extended lifetime. Hence, this developed dual-drug loaded hydrogel system has great potential in the intraoperative chemotherapy of gastric cancer, that suggests a clinically-relevant and valuable option for postsurgical management of gastric cancer.

Myocardial infarction (MI) leads to massive cardiomyocyte death and deposition of collagen fibers. This fibrous tissue disrupts electrical signaling in the myocardium, leading to cardiac systolic and diastolic dysfunction, as well as arrhythmias. Conductive hydrogels are a promising therapeutic strategy for MI. Here, we prepared a highly water-soluble conductive material (GP) by grafting polypyrrole (PPy) onto non-conductive gelatin. This component was added to the gel system formed by the Schiff base reaction between oxidized xanthan gum (OXG) and gelatin to construct an injectable conductive hydrogel. The prepared self-healing OGGP3 (3 wt% GP) hydrogel had good biocompatibility, elastic modulus, and electrical conductivity that matched the natural heart. The prepared biomaterials were injected into the rat myocardial scar tissue 2 days after MI. We found that the cardiac function of the rats treated with OGGP3 was improved, making it more difficult to induce arrhythmias. The electrical resistivity of myocardial fibrous tissue was reduced, and the conduction velocity of myocardial tissue was increased. Histological analysis showed reduced infarct size, increased left ventricular wall thickness, increased vessel density, and decreased inflammatory response in the infarcted area. Our findings clearly demonstrate that the OGGP3 hydrogel attenuates ventricular remodeling and inhibits infarct dilation, thus showing its potential for the treatment of MI.

Fatty liver disease has become one of the common liver diseases seriously affecting people’s health and quality of life. Existing means to quantify liver fat content are usually invasive and high-cost. Our research aims to design a single-sided magnet to develop a low-cost, noninvasive, and lightweight unilateral magnetic resonance (UMR) system that can satisfy the needs for fatty liver screening and diagnosis. A novel single-sided permanent magnet with a pear-shaped magnetic field iso-surface was designed to avoid the excitation of subcutaneous tissue in the human body. The weight of the magnet was optimized to 12.9 kg, and the mean magnetic field strength of the region of interest (ROI) was 0.07 T. The radio frequency (RF) coil set, the pulse sequence, and the modeling method for measuring proton density fat fraction (PDFF) were also introduced. Experiments for phantoms and volunteers were carried out by the UMR system to verify the performance of detection. The phantom detection results show that the UMR system can effectively avoid the influence of the subcutaneous tissue part on PDFF detection, with reasonable accuracy (around 5% fat fraction error) and robustness (within 10% relative error). Compared with a conventional magnetic resonance imaging (MRI) scanner, measurement results of volunteers (around 3% fat fraction error) show the effectiveness of the UMR system for screening fatty liver diseases. The UMR system developed based on the proposed portable single-sided magnet could be a low-cost and reliable diagnostic tool for noninvasive fatty liver disease diagnosis.

Kidney ischemia reperfusion injury (IRI) is a common and inevitable pathological condition in routine urological practices, especially during transplantation. Severe kidney IRI may even induce systemic damage to peripheral organs, and lead to multisystem organ failure. However, no standard clinical treatment option is currently available. It has been reported that kidney IRI is predominantly associated with abnormally increased endogenous reactive oxygen species (ROS). Scavenging excessive ROS may reduce the damage caused by oxidative stress and subsequently alleviate kidney IRI. Here, we reported a simple and efficient one-step synthesis of gold-platinum nanoparticles (AuPt NPs) with a gold core having a loose and branched outer platinum shell with superior ROS scavenging capacity to possibly treat kidney IRI. These AuPt NPs exhibited multiple enzyme-like anti-oxidative properties simultaneously possessing catalase- and peroxidase-like activity. These particles showed excellent cell protective capability, and alleviated kidney IRI both in vitroand in vivowithout obvious toxicity, by suppressing cell apoptosis, inflammatory cytokine release, and inflammasome formation. Meanwhile, AuPt NPs also had an effect on inhibiting the transition to chronic kidney disease by reducing kidney fibrosis in the long term. Thus, AuPt NPs might be a good therapeutic agent for kidney IRI management and may be helpful for the development of clinical treatments for kidney IRI.

The traditional Chinese herb hawthorn is gaining attention for its potential to lower lipid levels due to its active components that positively influence lipid metabolism. Our meta-analysis of fourteen randomized controlled trials compared traditional Chinese medicine containing hawthorn with conventional lipid-lowering drugs for hyperlipidemia. Hawthorn-based medicine showed promise in reducing total cholesterol and triglycerides while increasing high-density lipoprotein cholesterol levels, albeit less effective than standard drugs in lowering low-density lipoprotein cholesterol. However, caution is needed due to methodological limitations in some trials, emphasizing the importance of further well-designed studies to clarify hawthorn’s efficacy in managing hyperlipidemia.

Cancer is a serious threat to humans due to its high mortality. The efforts to fully understand cancer and to fight against it have never been stopped. The traditional therapies, such as surgery, radiotherapy and chemotherapy, are useful but cannot meet the increasing demands of patients. As such, novel approaches against cancer are urgently required. It has been found that the acidic tumor microenvironment plays important roles in promoting the cancer progression. In recent years, sodium bicarbonate (NaHCO3), a simple inorganic salt, has been found to be able to reverse the pH of tumor microenvironment and inhibit the invasion, metastasis, immune evasion, drug resistance and hypoxia of tumor cells. Thus, NaHCO3-based therapy is a potential approach for the treatment of cancer, and the related studies have been increasingly reported. Herein, we aim to provide a comprehensive understanding of the acidic tumor microenvironment and summarize the applications and mechanisms of NaHCO3in cancer therapy. The combination of NaHCO3with chemotherapy, immunotherapy or nanoparticles systems is discussed. In addition, the concerns of NaHCO3in clinical use and the potential ways to use NaHCO3for cancer therapy are also discussed.

The immunosuppressive tumor microenvironment (TME) of cancer strongly hinders the anti-tumor immune responses, thereby resulting in disappointing responses to immunotherapy. Chemoattractive and promotive traits of chemokines exerted on leukocytes have garnered interest in improving the efficiency of immunotherapy by increasing the infiltration of immune cells in the TME. In this study, a folic acid (FA) -modified gene delivery system based on the self-assembly of DOTAP, MPEG-PCL-MPEG, and FA-PEG-PCL-PEG-FA, namely F-PPPD, was developed to deliver plasmids encoding the immunostimulating chemokine CKb11. The delivery of plasmid CKb11 (pCKb11) by F-PPPD nanoparticles resulted in the high secretion of CKb11 from tumor cells, which successfully activated T cells, suppressed the M2 polarization of macrophages, promoted the maturation of dendritic cells (DCs), facilitated the infiltration of natural killer (NK) cells and inhibited the infiltration of immunosuppressive cells in tumor tissues. Administration of F-PPPD/pCKb11 also significantly suppressed the cancer progression. Our study demonstrated a nanotechnology-enabled delivery of pCKb11, that remodeled the immunosuppressive TME, for cancer treatment.

Biological applications of nanomaterials as delivery carriers have been embedded in traditional biomedical research for decades. Despite lagging behind, recent significant breakthroughs in the use of nanocarriers as tools for plant biotechnology have created great interest. In this Perspective, we review the outstanding recent works in nanocarrier-mediated plant transformation and its agricultural applications. We analyze the chemical and physical properties of nanocarriers determining their uptake efficiency and transport throughout the plant body. This perspective reviews and explores the customized design of “smart” nanocarriers for revolutionizing plant biotechnology in transformation and in agricultural applications, and discusses the challenges and tactical approaches for adapting biomedical nanocarriers for these purposes

The protein chromosome region maintenance 1 (CRM1) is an important nuclear export factor and drug target in diseases such as cancer and viral infections. Several plant-derived CRM1 inhibitors including plumbagin and oridonin possess potent antitumor activities. However, their modes of CRM1 inhibition remain unclear. Here, a multimutant CRM1 was engineered to enable crystallization of these two small molecules in its NES groove. Plumbagin and oridonin share the same three conjugation sites in CRM1. In solution, these two inhibitors targeted more CRM1 sites and inhibited its activity through promoting its aggregation, in addition to directly targeting the NES groove. While the plumbagin-bound NES groove resembles the NES-bound groove state, the oridonin complex reveals for the first time a more open NES groove. The observed greater NES groove dynamics may improve cargo loading through a “capture-and-tighten” mechanism. This work thus provides new insights on the mechanism of CRM1 inhibition by two natural products and a structural basis for further development of these or other CRM1 inhibitors.

Fibrosis occurs due to the excessive deposition of extracellular matrix caused by cell injury. After various types of tissue injury, the dysregulation of the internal response can eventually lead to the destruction of organ structure and dysfunction. There is increasing evidence that oxidative stress, which is characterized by excessive production of hydrogen peroxide (H2O2), is an important cause of fibrosis. Therefore, we synthesized a biosensitive and efficient electrochemical H2O2sensor based on PtNi nanoparticle-doped N-reduced graphene oxide (PtNi-N-rGO) to detect H2O2released from transforming growth factor β1 (TGFβ1)-induced myofibroblast. In addition, the sensor could easily detect changes in H2O2in the lung and bronchoalveolar lavage fluid (BALF) of mice with pulmonary fibrosis. Furthermore, the sensor could also detect H2O2in activated hepatic stellate cells and the liver of carbon tetrachloride (CCl4)-induced liver fibrosis. Moreover, the alterations in H2O2detected by the sensor were consistent with nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) protein expression and the staining results of pathological sections. Taken together, these results highlight the use of H2O2sensors for the rapid detection of fibrosis and facilitate the rapid evaluation of antifibrotic drug candidates.

Diabetes Wound Dressing In article 2303042, Zhiyong Qian and co‐workers report a multifunctional hydrogel wound dressing for diabetic wounds infected with bacteria. This hydrogel dressing exhibit excellent antibacterial properties, adhesion, and mild stimulation‐triggered detachment, offering a potential avenue for the development of painless antibacterial dressings.

The healing of chronic diabetic wounds is a common and significant challenge in the medical field. Despite extensive efforts, the development of hydrogel dressings with satisfactory functionality remains an ongoing concern. In this study, a multifunctional hydrogel wound dressing (PAN/Ag‐PLG) with adhesion, antibacterial, hemostatic, and other properties, which can effectively repair diabetic wounds infected with methicillin‐resistant Staphylococcus aureus(MRSA), is presented. The hydrogel dressing is composed of gallic acid (GA)‐functionalized polylysine (PL)‐reduced silver nanoparticles (Ag‐PLG), oxidized hyaluronic acid (OHA), and cross‐linked polyacrylic acid grafted with N‐hydrosuccinimide ester. Notably, compared to most conventional wound dressing that lack adhesion or are difficult to remove, the prepared hydrogels exhibit excellent adhesion and mild stimulation‐triggered detachment. In vitro and in vivo experiments reveal that the PAN/Ag‐PLG hydrogel exhibits outstanding biocompatibility and antibacterial properties and promotes diabetic wound repair by reducing oxidative damage and promoting cell migration and angiogenesis. The smart PAN/Ag‐PLG hydrogel reported in this study provides an approach for the potential clinical development of painless antibacterial dressings. A PAN/Ag‐PLG hydrogel with controllable adhesion and antimicrobial properties is developed. The hydrogel exhibits adhesion and gentle stimulus‐triggered detachment, outstanding biocompatibility, and promoted diabetic wound healing by reducing oxidative damage, promoting cell migration, and facilitating blood‐vessel formation. This study provides a potential approach for the clinical development of painless antimicrobial dressings.

With the incidence of neurodevelopmental disorders on the rise, it is imperative to screen and evaluate developmental neurotoxicity (DNT) compounds from a large number of environmental chemicals and understand their mechanisms. In this study, DNT qualitative structure-activity relationship (QSAR) study was carried out for the first time based on DNT data of mammals and structural characterization of DNT compounds was preliminarily illustrated. Five different classification algorithms and two feature selection methods were used to construct prediction models. The best model had good predictive ability on the external test set, but a small application domain (AD). Through combining of three different models, both MCC and AD values were improved. Furthermore, electronical properties, van der Waals volume-related properties and S, Cl or P containing substructure were found to be associated with DNT through modeling descriptors analysis and structure alerts (SAs) identification. This study lays a foundation for further DNT prediction of environmental exposures in human and contributes to the understanding of DNT mechanism.Graphical Abstract

Because of the nontargeting release of anticancer drugs, conventional chemotherapy results in serious side effects and poor therapeutic outcomes. In addition, hypoxia situation in the tumor microenvironment also promotes the growth and metastasis of tumors. Multifunctional nanocarriers with stimuli-activation and hypoxia-relieving properties can help overcome some of these limitations. In this study, we have constructed a nanocarrier which is named PBMn–DOX@RBC. A Prussian blue/manganese dioxide (PBMn) nanoparticle is used as an oxygen precursor or catalyzer for H2O2activation, and a red blood cell (RBC) membrane is used to increase the loading capacity of doxorubicin (DOX) and prolong the circulation time in vivo. H2O2is overproduced in tumor tissues and tumor cells. It can be used as a stimulus to activate drug release. In the presence of H2O2, the hypoxia inside the tumors is relieved by the administration of PBMn–DOX@RBC. The generated oxygen disrupts the RBC coated on the surface of PBMn, which accelerates the release of DOX. RBCs also prolong the circulation time of the nanometer system in vivo. By combining the photothermal therapy (PTT) and chemotherapy, the tumor growth inhibition mediated by PBMn–DOX@RBC is further enhanced. PBMn–DOX@RBC fulfills the demands to relieve tumor hypoxia and enhance cancer chemotherapy/PTT.

In our study, a hybrid alginate hydrogel cross-linked by calcium gluconate crystals deposited in poly(ε-caprolactone)-b-poly(ethylene glycol)-b-poly(ε-caprolactone) (PCL-PEG-PCL, abbreviated as PCEC) porous microspheres was developed for skin engineering. The diameter of microspheres was ∼212 μm, and the pore size was ∼8 μm. The PCEC porous microspheres supplied different functions in the hydrogel: (1) Calcium gluconate crystals were loaded in the inner pores of the microspheres, which can induce alginate hydrogel to cross-link in a few minutes once they were mixed. (2) The porous structure of the microspheres provided more anchor points for fibroblast attachment and growth, resulting in the enhancement of cell growth in the hybrid hydrogel. The PCEC microspheres/Alg hydrogel (MPs/Alg hydrogel) possessed excellent compatibility, because cell viability remained around 100% even at a concentration of 500 μg/mL. Meanwhile, the morphology of 3T3 and L929 cells attached on both PCEC porous microspheres and MPs/Alg hydrogel were confirmed by confocal laser spectrometry (CLSM). What’s more, MPs/Alg hydrogel promoted wound regeneration in a full-thickness skin defect model of rats. The mild inflammation reaction existed at the early stage of wound repair and gradually disappeared. These findings suggested that MPs/Alg hydrogel may possess great potential in the application of skin tissue engineering.

Controlled and rapid vascularization of engineered tissues remains one of the main challenges for tissue engineering. The immobilization of peptides and other bioactive molecules on the scaffolds has been demonstrated to be able to improve vascularization. However, the density of peptides modified on the scaffold surface is an important factor influencing vascularization. Thus, regulating the coupling efficiency of peptides may be an effective way to adjust vascularization. In this study, two-dimensional (2D) silk fibroin (SF) films and three-dimensional (3D) porous SF scaffolds with different secondary structure were prepared and coupled with Arg-Glu-Asp-Val (REDV) peptide. Compared with the high crystalline scaffolds, more peptides were bound on the scaffolds with low crystalline both in 2D and 3D forms with the result that more endothelial cells adhered on the low crystalline SF scaffolds. In addition, the in vivo angiogenic assays demonstrated that the low crystalline scaffolds showed higher blood vessel density after 28 days of implantation, which was 1.4-times as much as that of the high crystalline group. The results indicated that the peptide density could be controlled by SF structure and that the low crystalline SF scaffolds modified with REDV peptide could be a potential candidate for inducing angiogenesis in tissue engineering applications.

Camptothecin (CPT) exhibits potent antitumor activity; however, its clinical application is limited by significant gastrointestinal adverse effects (GAEs). Although the severity of GAEs associated with CPT derivatives has decreased, the incidence rate of these adverse effects has remained high. CPT multifunctional nanoparticles (PCRHNs) have the potential to increase the efficacy of CPT while reducing side effects in major target organs; however, the impact of PCRHNs on the GAEs from CPT remains uncertain. Here, we investigated the therapeutic effects of PCRHNs and different doses of CPT and examined their impacts on the intestinal barrier and the intestinal microbiota. We found that the therapeutic efficacy of PCRHNs+Laser treatment was superior to that of high-dose CPT, and PCRHNs+Laser treatment also provided greater benefits by helping maintain intestinal barrier integrity, intestinal microbiota diversity, and intestinal microbiota abundance. In summary, compared to high-dose CPT treatment, PCRHNs+Laser treatment can effectively balance therapeutic effects and GAEs. A high dose of CPT promotes the enrichment of the pathogenic bacteria Escherichia-Shigella, which may be attributed to diarrhea caused by CPT, thus leading to a reduction in microbial burden; additionally, Escherichia-Shigellarapidly grows and occupies niches previously occupied by other bacteria that are lost due to diarrhea. PCRHNs+Laser treatment increased the abundance of Lactobacillus(probiotics), possibly due to the photothermal effect of the PCRHNs. This effect increased catalase activity, thus facilitating the conversion of hydrogen peroxide into oxygen within tumors and increasing oxygen levels in the body, which is conducive to the growth of facultative anaerobic bacteria.

Conventional magnetic sensors usually employ Fe-based magnetic materials as signal probes. In this work, we find that Cu(II) is also a useful longitudinal relaxation time (T1) signal-based magnetic probe. We adopt bathocuproinedisulfonic acid disodium salt hydrate (BCS) to chelate Cu(I) and form a stable Cu(I)–BCS complex in aqueous solution and find the significant difference in the T1value of water protons between Cu(II) aqueous solution and Cu(I)–BCS complex aqueous solution. Redox reaction can convert Cu(II) to Cu(I) followed by the complexation of BCS, which results in apparent change of T1that can serve as magnetic signal readout, which is the basis of this Cu-T1sensor. Many redox reactions between Cu(II) and Cu(I) allow this Cu-T1sensor to not only realize “one-step mode” assay such as ascorbic acid, protein, and alkaline phosphatase but also enable “multi-step mode” immunoassay, such as biomacromolecules and small molecules. This Cu-T1sensor employs Cu ion as signal readout, providing an alternative tool for biochemical analysis.

Immunotherapy has achieved prominent clinical efficacy in combating cancer and has recently become a mainstream treatment strategy. However, achieving broad efficacy with a single modality is challenging, and the heterogeneity of the tumor microenvironment (TME) restricts the accuracy and effectiveness of immunotherapy strategies for tumors. Herein, a TME-responsive targeted nanoparticle to enhance antitumor immunity and reverse immune escape by codelivering interleukin-12 (IL-12) expressing gene and colony-stimulating factor-1 receptor (CSF-1R) inhibitor PLX3397 (PLX) is presented. The introduction of disulfide bonds and cyclo(Arg-Gly-Asp-d-Phe-Lys) (cRGD) peptides conferred reduction reactivity and tumor targeting to the nanoparticles, respectively. It is hypothesized that activating host immunity by the local expression of IL-12, while modulating the tumor-associated macrophages (TAM) function through blocking CSF-1/CSF-1R signaling, could constitute a feasible approach for cancer immunotherapy. The fabricated functional nanoparticle successfully ameliorated the TME by stimulating the proliferation and activation of T lymphocytes, promoting the repolarization of TAMs, reducing myeloid-derived suppressor cells (MDSCs), and promoting the maturation of dendritic cells (DC) as well as the secretion of antitumor cytokines, which efficiently suppressed tumor growth and metastasis. Finally, substantial changes in the TME were deciphered by single-cell analysis including infiltration of different cells, transcriptional states, secretory signaling and cell–cell communications. These findings provide a promising combinatorial immunotherapy strategy through immunomodulatory nanoparticles.

In recent years, Non-Hodgkin lymphoma (NHL) has been one of the most fast-growing malignant tumor diseases. NHL poses severe damages to physical health and a heavy burden to patients. Traditional therapies (chemotherapy or radiotherapy) bring some benefit to patients, but have severe adverse effects and do not prevent relapse. The relevance of emerging immunotherapy options (immune-checkpoint blockers or adoptive cellular methods) for NHL remains uncertain, and more intensive evaluations are needed. In this work, inspired by the idea of vaccination to promote an immune response to destroy tumors, we used a biomaterial-based strategy to improve a tumor cell-based vaccine and constructed a novel vaccine named Man-EG7/CH@CpG with antitumor properties. In this vaccine, natural tumor cells are used as a vector to load CpG-ODN, and following lethal irradiation, the formulations were decorated with mannose. The study of the characterization of the double-improved vaccine evidenced the enhanced ability of DCs targeting and improved immunocompetence, which displayed an antitumor function.

Diabetic skin ulcer is one of the severe complications of diabetes mellitus, which has a high incidence and may cause death or disability. Platelet-rich plasma (PRP) is widely used in the treatment of diabetic wounds due to the effect of growth factors (GFs) derived from it. However, the relatively short half-life of GFs limits their applications in clinics. In addition, the presence of a large amount of proteases in the diabetic wound microenvironment results in the degradation of GFs, which further impedes angiogenesis and diabetic wound healing. In our study, we fabricated a self-healing and injectable hydrogel with a composite of chitosan, silk fibroin, and PRP (CBPGCTS–SF@PRP) for promoting diabetic wound healing. CBPGCTS–SF@PRP could protect PRP from enzymatic hydrolysis, release PRP sustainably, and enhance the chemotaxis of mesenchymal stem cells. The results showed that it could promote the proliferation of repair cells in vitro. Moreover, it could enhance wound healing by expediting collagen deposition, angiogenesis, and nerve repair in a type 2 diabetic rat model and a rat skin defect model. We hope that this study will offer a new treatment for diabetic nonhealing wounds in clinics.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a respiratory disease called coronavirus disease 2019 (COVID-19), the spread of which has led to a pandemic. An effective preventive vaccine against this virus is urgently needed. As an essential step during infection, SARS-CoV-2 uses the receptor-binding domain (RBD) of the spike protein to engage with the receptor angiotensin-converting enzyme 2 (ACE2) on host cells1,2. Here we show that a recombinant vaccine that comprises residues 319–545 of the RBD of the spike protein induces a potent functional antibody response in immunized mice, rabbits and non-human primates (Macaca mulatta) as early as 7 or 14 days after the injection of a single vaccine dose. The sera from the immunized animals blocked the binding of the RBD to ACE2, which is expressed on the cell surface, and neutralized infection with a SARS-CoV-2 pseudovirus and live SARS-CoV-2 in vitro. Notably, vaccination also provided protection in non-human primates to an in vivo challenge with SARS-CoV-2. We found increased levels of RBD-specific antibodies in the sera of patients with COVID-19. We show that several immune pathways and CD4 T lymphocytes are involved in the induction of the vaccine antibody response. Our findings highlight the importance of the RBD domain in the design of SARS-CoV-2 vaccines and provide a rationale for the development of a protective vaccine through the induction of antibodies against the RBD domain.

The prevalence of skin cancer is rising along with the rapid population aging in recent years. Traditional therapies, such as surgical treatment, radiotherapy, chemotherapy, photodynamic therapy, and immunotherapy, may accompany serious side effects, limiting their clinical benefits. According to the biological characteristics of skin cancer, we have already established two kinds of synergetic systems of photothermal therapy (microneedle) and chemotherapy, containing gold nanorods (GNR). Although the microneedle system exhibited great potential for skin cancer treatment, the system could be still improved further. So, we designed a near-infrared light-responsive 5-fluorouracil (5-Fu) and indocyanine green (ICG) loaded monomethoxy-poly (ethylene glycol)-polycaprolactone (MPEG-PCL) nanoparticle (5-Fu-ICG-MPEG-PCL), and then 5-Fu-ICG-MPEG-PCL was integrated with a hyaluronic acid dissolvable microneedle system (HA MN) to get 5-Fu-ICG-MPEG-PCL loaded HA MN for treating skin cancers, including human epidermoid cancer and melanoma. In this system, hyaluronic acid, the microneedle carrier, possesses good skin penetration ability and is approved by FDA as a pharmaceutical adjuvant; 5-Fu is recommended by FDA for skin cancer treatment; ICG, a photothermal agent, possesses a strong photothermal ability and is approved by FDA for its use in the human body. We hypothesized that 5-Fu-ICG-MPEG-PCL could be delivered by the dissolvable microneedle through the skin, and the release behavior of the drug in the nanoparticle could be controlled by near-infrared light for achieving a single-dose cure of skin cancer, improving the cure rate of skin cancer and providing a new idea and possibility for the clinical treatment of skin cancer.

We report here the fabrication of 3D porous acellular cartilage scaffold, and its coating with poly(L-lysine)/hyaluronic acid (PLL/HA) multilayer film. The multilayer coated porous scaffold was further loaded with TGF-β3, which underwent sustainable release up to 60 days in vitro.

In this review, the synthesis methods and influencing factors of synthesize Ag2S NPs with different sizes were compared firstly, and then the photothermal effect and fluorescence characteristics of Ag2S NPs with different sizes were summarized. Finally, the possibilities and challenges of using Ag2S NPs to construct theranostic agent were discussed in the end.

Biomaterial implantation is followed by an inflammatory cascade dominated by the macrophages, which polarized to the proinflammation M1 phenotype or prohealing M2 phenotype. Generally, silk sericin (SS) is considered to be of high immunogenicity associated with native silk fibers. The blends of silk fibroin (SF) and SS in different mass ratios might elicit different host immune responses and induce macrophage phenotype switch. The objective of this study was to assess the effects of electrospun SF–SS fibrous films with different mass ratios (10:0, 9:1, 8:2, and 7:3) on the macrophage phenotypes and explore the optimal ratio of SF and SS for angiogenesis. Our results indicated that the macrophages were activated by the addition of SS. When the mass ratio of SF and SS reached 7:3, the film displayed the highest degree of vascularization. The macrophages were induced to secrete more M1 and M2 cytokines accompanying with high M2/M1 ratio. Taken together, this study provided a perspective to promote neovascularization by modulating appropriate host response and macrophage phenotypes in tissue engineering field.

Oral tyrosine kinase inhibitors (TKIs) against epidermal growth factor receptor (EGFR) family have been introduced into the clinic to treat human malignancies for decades. Despite superior properties of EGFR-TKIs as small molecule targeted drugs, their applications are still restricted due to their low solubility, capricious oral bioavailability, large requirement of daily dose, high binding tendency to plasma albumin and initial/acquired drug resistance. Nanotechnology is a promising tool to improve efficacy of these drugs. Through non-oral routes. Various nanotechnology-based delivery approaches have been developed for providing efficient delivery of EGFR-TKIs with a better pharmacokinetic profile and tissue-targeting ability. This review aims to indicate the advantage of nanocarriers for EGFR-TKIs delivery.

Glioma treatment using targeted chemotherapy is still far from satisfactory due to not only the limited accumulation but also the multiple survival mechanisms of glioma cells, including up-regulation of both autophagy and programmed cell death ligand 1 (PD-L1) expression. Herein, we proposed a combined therapeutic regimen based on functional gold nanoparticles (AuNPs)-enabled chemotherapy, autophagy inhibition, and blockade of PD-L1 immune checkpoint. Specifically, the legumain-responsive AuNPs (D&H-A-A&C) could passively target the glioma site and form in situ aggregates in response to legumain, leading to enhanced accumulation of doxorubicin (DOX) and hydroxychloroquine (HCQ) at the glioma site. HCQ could inhibit the DOX-induced cytoprotective autophagy and thus resensitize glioma cells to DOX. Parallelly, inhibiting autophagy could also inhibit the formation of autophagy-related vasculogenic mimicry (VM) by glioma stem cells. In vivo studies demonstrated that D&H-A-A&C possessed promising antiglioma effect. Moreover, cotreatment with anti-PD-L1 antibody was able to neutralize immunosuppressed glioma microenvironment and thus unleash antiglioma immune response. In vivo studies showed D&H-A-A&C plus anti-PD-L1 antibody could further enhance antiglioma effect and efficiently prevent recurrence. The effectiveness of this strategy presents a potential avenue to develop a more effective and more personalized combination therapeutic regimen for glioma patients.

Bacterial infection of wounds is an escalating medical problem, issuing threats to both global public health and personal health. Photothermal antibacterial technology as a novel sterilization strategy has outstanding sterilization efficiency, high safety and low risk of emergence of drug-resistant bacteria. By combining inherent antibacterial activity and light-assisted antibacterial treatment, developing novel multifunctional dressings with synergistic high-efficiency antibacterial effects and also promoting wound healing possesses attractive advantages in the field of treating bacterial wound infections in clinical care. Herein, a multifunctional hydrogel formed by in situphoto-cross linking was designed and prepared by first grafting methacrylic anhydride as a photosensitizer onto chitosan, and then introducing oxidatively synthesized polydopamine (PDA). The physicochemical characterizations of the synthesized hydrogels demonstrated their tunability certainly associated with PDA concentration, including pore size, water swelling, rheological properties and in vitrodegradability. In addition, the composite hydrogels exhibited good adhesion, anti-oxidation and photothermal properties due to the existence of PDA. Within 10 min upon exposure to 808 nm near-infrared (NIR) light irradiation, this hydrogel system displayed outstanding antibacterial activity against Staphylococcus aureuswith almost 100% killing efficiency, of which rapid efficient sterilization plays a significant role in wound healing. Moreover, the hydrogel is capable of cytocompatibility and has low toxicity to murine fibroblasts (L929 and NIH/3T3). In the full-thickness wound defect infection model in mice, the wound closure ratio, inflammatory response, fibroblasts, neovascularization and epithelialization were measured. Animal experiments also reveal that the hydrogel assisted with NIR laser irradiation can inhibit effectively infection at an early stage and accelerate the wound healing process. In summary, this novel multifunctional injectable hydrogel exhibits excellent swelling capacity, bio-adhesion, antioxidant property, photothermal activity, efficient antibacterial property and facilitates skin healing, which has great promising application as a medical dressing biomaterial in infected wound care fields.

Multidrug resistance (MDR) is still a formidable obstacle for the majority of anticancer drugs during chemotherapy. MDR is generally divided into the pump and nonpump resistances, which significantly and simultaneously reduce drug accumulation and potency in various cancer cells. In order to concurrently combat the two pathways to completely overcome MDR, a novel siRNA-containing nanomaterial-coated mitochondria complex was developed, which can overcome the barrier of activity loss and electrostatic repulsion to effectively deliver siRNA and mitochondria into the MDR cells. In this way, the functional siRNA could successfully down-regulate pump resistance-related proteins while the transplanted mitochondria efficaciously played its role to improve apoptotic signal activation and transmissions by means of restoring intracellular metabolism environment. We believe this unique organelle-material complex would hold great promise to reverse overall MDR as a result of high spatial-temporal synchronization of potent synthetic and living species.

Hydrogel is an ideal scaffold in the fields of regenerative medicine and tumor therapy because of its biomimetic ability to modulate tissue microenvironment. Herein, we fabricated a new kind of self-healing hydrogel based on graphene nanoparticle and expanded its application in postoperative recurrence of breast cancer. First, a facile method was used to prepare self-healing hydrogel via Schiff-base linkage, which composed of chondroitin sulfate multialdehyde (CSMA), branched polyethylenimine (BPEI) and BPEI conjugated graphene (BPEI-GO). BPEI-GO was doped in the network and participated in Schiff-base reaction and stabilized the structure, as well as provided sustained drug delivery, and near-infrared laser (NIR)-triggered photothermal effect. The hydrogels exhibited excellent self-healing (∼100%) and improved mechanical properties (7,000 Pa). Further, in vitro breast cancer cell inhibition study showed enhanced cell killing efficiency with synergistic chemo-photothermal therapy. In the breast cancer postoperative recurrence prevention mice model, we found that combination of Doxorubicin (DOX) and photothermal therapy in CSMA/BPEI/BPEI-GO hydrogels group reduced tumor recurrence to 33.3%, compared with 66.7% for DOX-loaded hydrogels without NIR irradiation, 66.7% for local administration of free DOX, 100% for hydrogels with NIR irradiation, blank hydrogels, and blank control. This study suggests the great potential of CSMA/BPEI/BPEI-GO hydrogels for postoperative recurrence prevention of breast cancer.

Codelivery nanovaccines of antigens and adjuvants have achieved positive therapy for cancer immunotherapy. The insufficient immunogenicity of these vaccines leads to the difficulty of eliciting robust immune effects for immune clearance due to the inadequate loading efficiency, complex preparation processes, low safety concerns, and weak immune responses. Herein, a visible codelivery nanovaccine of an antigen and adjuvant based on self-cross-linked antigen nanoparticles (ovalbumin nanoparticles (ONPs)) combined with the adjuvant (CpG) for cancer immunotherapy was prepared using antigens themselves as carriers. ONPs not only provide sufficient antigens for continuous simulation of the immune response with high antigen loading efficiency but also serve as natural carriers of CpG. In vitro and in vivo experiments proved that ONPs-CpG can elicit a robust immune response including DC maturity, T cell activation, and IFN-γ production. ONPs-CpG induced strong tumor-specific immunity and exhibited remarkable antitumor immunotherapy effects in vivo using mouse models of lymphoma. Furthermore, to perform the precise vaccine delivery, the dual fluorescent codelivery nanovaccine was monitored in real time in vivo by the visible imaging method. With regard to migration tracking, fluorescence imaging allowed for both high resolution and sensitivity of visible detection based on the fluorescence of ONPs and CpG. The multifunctional nanovaccine could function as a robust platform for cancer immunotherapy and a visible system for antigen–adjuvant tracking.

The CPT was loaded into the HMSNs with the high loading capacity. Then the CPT@HMSNs were loaded into the PLEL thermosensitive hydrogels for local therapy to prevent the recurrence of breast cancer after the tumor was resected.

Bone defects caused by trauma, infection or bone tumor resection, are highly prevalent. A small number (5%–10%) of these injuries fail to heal due to non-union and require surgical intervention. Currently, the principal treatment options for these defects are autografts, allografts, xenografts or synthetic grafts. The main problems associated with these therapies include pain, infection and donor site morbidity. Bone tissue engineering is a diverse field that focuses on the regeneration of bone by combining cells, scaffolds, growth factors and dynamic forces. There have been many recent studies utilizing biomineralized polymer matrix composites which mimic the natural structure of bone. The principal focus of this review is on recent advances in the synthesis of various types of biomineralized polymer matrix composite. Examples of the biomineralization of naturallyderived and synthetic polymers widely used for bone engineering are also summarized.

Ultrasonography is an important complement to clinical diagnosis, and the application of microbubbles effectively improved diagnostic accuracy in echography. In scientific research, the sizes of microbubbles range from nanometers to microns. By optimizing the fabrication process, bubble sizes and ultrasound parameters, microbubbles can also be used for drug delivery and therapeutic monitoring. In this review, we summarize the recent advances in the diagnosis and treatment of microbubbles according to their different components. Modification of microbubble shells allows for more accurate imaging and detection and the combined utilization of US-targeted MB destruction (UTMD) allows for non-invasive, precise and targeted delivery of drug molecules to pathological tissues. These features pave the way for the emerge of theranostic microbubbles by combination of functional compositions and the application of multifunctional materials. Theranostic microbubbles allow for the simultaneous process of diagnosis, visualization of drug delivery and therapeutic monitoring. Ultimately, theranostic microbubbles are promising in clinical practice and would enhance contrast-enhanced US (CEUS) to a new qualitative level.

Cancer immunotherapy harnesses the immune system to attack tumors and has received extensive attention in recent years. Cancer vaccines as an important branch of immunotherapy are designed for delivering tumor antigens to antigen-presenting cells (APCs) to stimulate a strong immune response to against tumors, representing a potentially therapeutic and prophylactic effect with the long-term anti-cancer benefits. Nevertheless, the disappointing outcomes of their clinical use might be attributed to dilemma in antigen selection, immunogenicity, lymph nodes (LNs) targeting ability, lysosomal escape ability, immune evasion, etc.Nanotechnology, aiming to overcome these barriers, has been utilized in cancer vaccine development for decades. Numerous preclinical and clinical studies demonstrate positive results in nanomaterials-based cancer vaccines with considerable improvement in the vaccine efficacy. In this review, we systematically introduced the characteristics of nanovaccines and highlighted the different types of nanomaterials used for cancer vaccine design. In addition, the opportunities and challenges of the emerging nanotechnology-based cancer vaccines were discussed.

The main challenge of paramagnetic ions-mediated magnetic sensors is their relatively low sensitivity. In this study, we observe the amplification of longitudinal relaxation time (T1) signal when Fe2+transforms into Fe3+followed by the coordination of potassium thiocyanate (KSCN) and develop a sensitive Fe-T1sensor based on the coordination chemistry between KSCN and Fe3+to amplify the T1signal for detecting a series of targets, such as hydrogen peroxide, glucose, and antigen/antibody. We justify the practicability of our assay by successfully detecting tetracycline in milk samples and hepatitis C virus in clinical samples with satisfactory accuracy. This KSCN-mediated Fe-T1sensor not only realizes biochemical analysis and immunoassay with higher sensitivity but also retains many advantages of paramagnetic ions-mediated magnetic sensors (good stability and straightforward operation), which holds great promise for the detection of a range of targets of interest in complex samples.

The colorimetric immunoassay based on gold nanoparticles (AuNPs) can hardly enable simultaneous detection of multiple biomarkers in vastly different concentrations (e.g., pg/mL−μg/mL) because of its narrow dynamic range. In this work, we demonstrate an immunoassay with tunable detection range by using peptide-mediated controlled aggregation of surface modification-free AuNPs. Alkaline phosphatase (ALP) removes the phosphate group of the peptide to yield a positively charged product, which triggers the aggregation of negatively charged AuNPs and the color change of the AuNPs solution from red to blue with naked-eye readout. We design and screen 20 kinds of phosphorylated peptides to obtain a broad and controllable detection range for ALP sensing and apply them for detecting multiple inflammatory biomarkers in clinical samples. Our assay realizes straightforward, multiplexed, and simultaneous detection of multiple clinical biomarkers with tunable detection range (from pg/mL to μg/mL) in the same run and holds great potential for chemical/biochemical analysis.

Spinal fusion is the classic treatment to achieve spinal stability for the treatment of the spinal disease. Generally, spinal fusion still has to combine a certain of bone matrix for promoting bone formation to achieve the desired fusion effect based on the surgery, including the traditional bone matrix, such as the autologous bone, allografts and xenografts. Nevertheless, some problems still existed such as the immunogenic problems, the secondary wound, and pathogenic transfer and so on. Here the injectable thermosensitive hydrogel could substitute to avoid the problems as a potential biological scaffold for tissue engineering. Once injected, they could fill in the irregular-shaped cavity and change to a gel state at physiological temperature. We wanted to design the collagen/n-HA/BMP-2@PCEC/PECE hydrogel composites based on previous work about collagen/n-HA/PECE hydrogel to exhibit better performance in guiding spinal fusion because of the addition of BMP-2@PCEC nanoparticles (PCEC, PCL-PEG-PCL). However, when the hydrogels were injected, one of the surfaces was in contact with the spine, but others were in contact with soft tissue like muscles and fascia. The release behavior was the same at the different surfaces, so the factors could be released into the soft tissue, and it may then be consumed or lead to ectopic bone formation. The hydrogel composites should be improved to adjust the direction of the releaser behavior. In consequence, we wrapped an electrostatic spinning nanofiber membrane possessing hydrophobicity around the hydrogels. In this study, we developed a system that the collagen/n-HA/BMP-2@PCEC/PECE hydrogels were wrapped with the hydrophobicity PDLLA electrospun nanofiber membrane, setting up a barrier between the hydrogels and the soft tissue. The system could exhibit biocompatibility, preventing the factors from escaping to keep their retention in the needed places of osteogenesis; the results demonstrated that it showed an excellent effect on spinal fusion.