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The proposed photoclick HC–HN bioink expands the palette of available polysaccharide-based bioinks and greatly extends the biofabrication window to broaden the application opportunities of 3D bioprinting.

Due to their inherent and tunable biomechanical and biochemical performances, bioactive hydrogels based on polysaccharides and peptides have shown attractive potential for wound management. In this review, the recent progress of bioactive hydrogels prepared by polysaccharides and peptides for soft tissue wound management is overviewed. Meanwhile, we focus on the elaboration of the relationship between chemical structures and inherent bioactive functions of polysaccharides and peptides, as well as the strategies that are taken for achieving multiple wound repairing effects including hemostasis, adhesion, wound contraction and closure, anti-bacteria, anti-oxidation, immunomodulation, molecule delivery

Three-dimensional (3D) bioprinting has played an increasingly crucial role in the manufacturing of organized complex tissues and organs, which has shown tremendous potential in the field of tissue engineering. Extrusion-based bioprinting takes advantage of its competitive pricing and flexibility to print various biomaterials, and it has now developed into one of the most used printing techniques. However, extruding soft hydrogels, also known as bioinks, often leads to poor fidelity when printed in air. As an emerging printing approach, 3D embedded bioprinting deposits bioinks not on a platform but into a support bath, preventing constructs from settling and collapsing. This review discusses the challenges faced in the traditional 3D bioprinting of soft or low-viscosity bioinks and the changes brought by embedded bioprinting as an emerging solution. Particular focus is given to the progress of hydrogels used as bioinks and support baths. Finally, we highlight the challenges involved in this process and look forward to the prospects of this technology.

Tumor cells are dominant in the nutritional competition in the tumor microenvironment (TME), and their metabolic abnormalities often lead to microenvironmental acidosis and nutrient deprivation, thereby impairing the function of immune cells and diminishing the anti-tumor therapeutic effect. Herein, we report a branched polymeric conjugate and its efficacy in attenuating the metabolic competition of tumor cells. Compared with the control nanoparticles prepared from its linear counterpart, the branched conjugate-based nanoparticles (branched NPs) could more efficiently accumulate in the tumor tissue and interfere with the metabolic processes of tumor cells to increase the concentration of essential nutrients and reduce the level of immunosuppressive metabolites in the TME, thus creating a favorable environment for infiltrated immune cells. Its combined treatment with an immune checkpoint inhibitor (ICI) achieved an enhanced anti-tumor effect. Our work presents a promising approach for targeting the metabolic competition in the TME to enhance the chemo-immunotherapeutic effect against cancers. This article is protected by copyright. All rights reserved.

Background Nanocarriers-derived antitumor therapeutics are often associated with issues of limited tumor penetration and dissatisfactory antitumor efficacies. Some multistage delivery systems have been constructed to address these issues, but they are often accompanied with complicated manufacture processes and undesirable biocompatibility, which hinder their further application in clinical practices. Herein, a novel dual-responsive multi-pocket nanoparticle was conveniently constructed through self-assembly and cross-linking of amphiphilic methoxypolyethylene glycol-lipoic acid (mPEG-LA) conjugates to enhance tumor penetration and antitumor efficacy. Results The multi-pocket nanoparticles (MPNs) had a relatively large size of ~ 170 nm at physiological pH which results in prolonged blood circulation and enhanced accumulation at the tumor site. But once extravasated into acidic tumor interstices, the increased solubility of PEG led to breakage of the supramolecular nanostructure and dissolution of MPNs to small-sized (3) bearing mice with reduced side effect. Conclusions Our facile fabrication of multi-pocket nanoparticles provided a promising way in improving solid tumor penetration and achieving a great therapeutic efficacy. Graphic Abstract

Multi-modal therapeutics are emerging for simultaneous diagnosis and treatment of cancer. Polymeric carriers are often employed for loading multiple drugs due to their versatility and controlled release of these drugs in response to a tumor specific microenvironment. A theranostic nanomedicine was designed and prepared by complexing a small gadolinium chelate, conjugating a chemotherapeutic drug PTX through a cathepsin B-responsive linker and covalently bonding a fluorescent probe pheophorbide a (Ppa) with a branched glycopolymer. The branched prodrug-based nanosystem was degradable in the tumor microenvironment with overexpressed cathepsin B, and PTX was simultaneously released to exert its therapeutic effect. The theranostic nanomedicine, branched glycopolymer-PTX-DOTA-Gd, had an extended circulation time, enhanced accumulation in tumors, and excellent biocompatibility with significantly reduced gadolinium ion (Gd3+) retention after 96 h post-injection. Enhanced imaging contrast up to 24 h post-injection and excellent antitumor efficacy with a tumor inhibition rate more than 90% were achieved from glycopolymer-PTX-DOTA-Gd without obvious systematic toxicity. This branched polymeric prodrug-based nanomedicine is very promising for safe and effective diagnosis and treatment of cancer., Highlights • A cathepsin B-responsive theranostic nanomedicine (glycopolymer-PTX-DOTA-Gd) based on a branched glycopolymer was prepared. • Glycopolymer-PTX-DOTA-Gd can be specifically degradated and release drug at tumor enviornment. • Glycopolymer-PTX-DOTA-Gd enhance the contrast of magnetic resonance imaging (MRI) at tumor sites. • The nanomedicine have good biocompatibility, excellent tumor targeting and anti-tumor efficacy., Graphical abstract Cathepsin B-responsive biodegradable branched glycopolymer-based prodrug was designed and prepared as theranostic nanomedicine for cancer treatments, resulting in significantly enhanced therapeutic indexes and strengthened contrast of magnetic resonance imaging (MRI) at tumor sites.Image 1

Dendron-polymer-based nanoscale and stimuli-responsive drug delivery systems have shown great promise in tumor-targeting accumulation without significant toxicity. Here we report a dendronized polymer-doxorubicin (DOX) hybrid (DPDH) with an improved in vivo drug delivery efficiency for cancer therapy compared with a linear polymer-DOX conjugate (LPDC). The in vitro drug release profile of DOX indicates that DPDH displays pH-responsive drug release due to cleavage of hydrazone bonds since a greater amount of DOX is released at pH 5.2 at a faster rate than at pH 7.4. DPDH efficiently enters 4T1 cells and releases DOX to induce cytotoxicity and apoptosis. Owing to the dendronzied structure, DPDH has a significantly longer blood circulation time than LPDC. DPDH substantially enhances the therapeutic efficacy to suppress tumor growth in a 4T1 mammary cancer model than LPDC as well as free drug, evidenced from tumor growth inhibition, TUNEL assessment and histological analysis. Biosafety of DPDH is also confirmed from hemolysis, body weight shifts during treatment and pathological analysis. This study demonstrates the use of dendronized polymer-DOX hybrids for specific drug molecules is a promising approach for drug delivery.

Although tissue adhesives have potential advantages over traditional sutures, existing ones suffer from several limitations: slow adhesion kinetic, low mechanical strength, and poor interfacial bonding with wet biological tissues. Herein, a cooperative mussel/slug double-bioinspired hydrogel adhesive (DBHA) composed of a robust adhesive interface and a stretchable dissipative matrix is developed. The DBHA is formed by a cationic polysaccharide (chitosan), an anionic polysaccharide (carboxymethyl cellulose), and a barbell-like dendritic lysine grafted with catechol groups (G3KPCA). Compared to various commercial bio-glues and traditional adhesives, the DBHA has significantly stronger tissue adhesion and enhanced toughness both ex vivo and in vivo. Meanwhile, the DBHA exhibits fast, strong, tough, and durable adhesion to diverse ex vivo tissue surfaces with blood. The adhesion energy between the adhesive and porcine skin can reach 200-900 J m

To improve the response rate of immune checkpoint inhibitors such as anti-PD-L1 antibody in immunosuppressive cancers like triple-negative breast cancer (TNBC), induction of immunogenic cell death (ICD) at tumor sites can increase the antigenicity and adjuvanticity to activate the immune microenvironment so that tumors become sensitive to the intervention of immune checkpoint inhibitors. Herein, a self-amplified biomimetic nanosystem, mEHGZ, was constructed by encapsulation of epirubicin (EPI), glucose oxidase (Gox) and hemin in ZIF-8 nanoparticles and coating of the nanoparticles with calreticulin (CRT) over-expressed tumor cell membrane. EPI acts as an ICD inducer, Gox and hemin medicate the cascade generation of reactive oxygen species (ROS) to strengthen the ICD effect, and CRT-rich membrane as "eat me" signal promote presentation of the released antigens by dendritic cells (DCs) to invoke the tumor-immunity cycle. The biomimetic delivery system displays an amplified ICD effect via Gox oxidation, hydroxyl radical generation and glutathione (GSH) depletion. The induced potent ICD effect promotes DCs maturation and cytotoxic T lymphocytes (CTLs) infiltration, reversing an immunosuppressive tumor microenvironment to an immunoresponsive one. Treatment with the nanosystem in combination with anti-PD-L1 antibody results in distinctive inhibition of tumor growth and lung metastasis, supporting that a potent ICD effect can significantly boost the therapeutic efficacy of the anti-PD-L1 antibody. This self-amplified biomimetic nanoplatform offers a promising means of raising the response rate of immune checkpoint inhibitors.

Cancer theranostics is a new strategy for combating cancer that integrates cancer imaging and treatment through theranostic agents to provide an efficient and safe way to improve cancer prognosis. Design and synthesis of these cancer theranostic agents are crucial since these agents are required to be biocompatible, tumor-specific, imaging distinguishable and therapeutically efficacious. In this regard, several types of gadolinium (Gd)-based nanomaterials have been introduced to combine different therapeutic agents with Gd to enhance the efficacy of therapeutic agents. At the same time, the entire treatment procedure could be monitored via imaging tools due to incorporation of Gd ions, Gd chelates and Gd/other imaging probes in the theranostic agents. This review aims to overview recent advances in the Gd-based nanomaterials for cancer theranostics and perspectives for Gd nanomaterial-based cancer theranostics are provided.

The controllable synthesis and customized design of micro/nanomotors represents a highly desired paradigm in the field of intelligent nanovehicles. Exploiting asymmetrical structures and geometry-dependent propulsion are the two main strategies for achieving light-driven micro/nanomotors. However, inherent crystal-structure differences in a single colloidal motor have rarely been explored. Here, we propose the first surface-heterojunction-induced propulsion methodology for cuprous oxide (Cu2O) nanomotors, by tailoring the crystal morphology of a Cu2O crystalloid from a sphere into a truncated octahedron and preserving the controllable-index crystal facets of {100} and {111} in a single colloid. Due to the high crystallinity and distinct activity of the exposed crystal facets, a surface heterojunction between the {100} and {111} facets is formed to enhance electron-hole separation, as confirmed by density functional theory (DFT) calculations, thus endowing the truncated octahedral Cu2O nanomotors with autonomous and vigorous movement in biocompatible fuels under visible light. These Cu2O nanomotors can reach a propulsion speed in water of over two times faster than that of polycrystalline spherical motors with low crystallinity. The efficient Cu2O nanomotors offer a promising guideline not only for the synthesis of novel light-driven motors with desired structures, but also for potential applications in biocompatible environments.

Combination therapy has exhibited crucial potential in the treatment of cancers, especially in drug-resistant cancers. In this work, a novel tumor-targeted, redox dual-responsive and paclitaxel (PTX) loaded nanoparticle based on multifunctional dendrimer and lentinan was developed for combinational chemo-photodynamic therapy of PTX-resistant cancers. The nanoparticles exhibited enhanced cellular uptake and tumor penetration based on phenylboronic acid-sialic acid interactions, and had the ability to control drug release in response to intracellular high concentration of glutathione and H2O2. Specifically, light irradiation not only triggered the photodynamic effect of the nanoparticles for prominent photodynamic cytotoxicity, but also resulted in increased internalization and accelerated release of PTX into cytoplasm through the lysosome disruption, as well as the obvious damage to microtubules and actin microfilaments, for drug resistance reversal of A549/T cells. Meanwhile, PTX treatment would arrest cells in G2/M phase, thereby prolonging the period when nuclear membrane is broken down, which further facilitated photosensitizer accumulation in nuclei and improved DNA damage response. Consequently, the combination of PTX and photodynamic treatment lead to excellent antitumor effects to drug-resistant A549/T cells in vitro and in vivo, which provides a new strategy for the design of co-delivery system to overcome drug resistance.

A hypoxic environment in tumors hampers the therapeutic efficacy of radiotherapy. Moreover, radiotherapy, a localized treatment technique, can barely control tumor metastases. Herein, poly(lactic-co-glycolic acid) was used to encapsulate perfluorocarbon (PFC) for increasing the oxygen level and a lignan-derived compound (Q1) for enhancing IL-25 secretion from fibroblasts, thereby boosting the radiotherapeutic effect on local and distant tumors. The prepared co-delivery nanoplatform, PFC-Q1@PLGA, has a nano-scale size of around 160 nm and a negative zeta potential (about -13 mV). PFC-Q1@PLGA treatment leads to an arrest of the G2 phase (4n) in the cell cycle and reduces the mitochondria membrane potential. A high expression level of IL-25 in fibroblasts is detected after the cells are treated with PFC-Q1@PLGA, which increases the late apoptosis percentage of 4T1 cells after treatment with IL-25-containing conditional medium from fibroblasts. The oxygen level in tumors is significantly promoted to about 52.3% after injection of oxygen-saturated PFC-Q1@PLGA (O2), which is confirmed from the functional magnetic resonance images of the tumor site in mice. The in vivo study demonstrates that the injection of PFC-Q1@PLGA (O2) into local tumors significantly enhances the radiotherapeutic effect on local tumors and also inhibits the growth of remote tumors by an enhanced abscopal effect. This study presents a novel radiotherapy strategy to enable synergistic whole-body therapeutic responses after localized treatment with PFC-Q1@PLGA (O2).

The architecture of multivalent polymers exerts an amplified interaction between attached ligands and targets. In current research, we reveal that a dendronized polymer augments the efficacy of an oncolytic peptide (OP; KKWWKKWDipK) for immunotherapy by exploiting (i) "flexible" linear polymer backbone to facilitate interactions with biomembrane systems, and (ii) "rigid" dendronized side chains to enhance the membrane lytic property. We show that a dendronized N-(2-hydroxypropyl)methacrylamide (HPMA) polymer-OP conjugate (PDOP) adopts α-helix secondary structure and induces robust immunogenic cell death (ICD) in cancer cells as characterized by multiple damage-associated molecular patterns (DAMPs) which include intracellular formation of reactive oxygen species (ROS) and surface exposure of calreticulin (CRT). These events convert immunosuppressive 4T1 tumor to an immunoresponsive one by recruiting CD8+ cytotoxic T cells into tumor beds. Combination of PDOP with anti-PD-L1 immune checkpoint blockade (ICB) increases the number of effector memory T cells and completely eradicates 4T1 tumors in mice. Our findings suggest that PDOP is a promising platform for oncolytic immunotherapy.

The development of natural polymer-based hydrogels, combining outstanding injectability, self-healing, and tissue adhesion, with mechanical performance, able to facilitate full-thickness skin wound healing, remains challenging. We have developed an injectable micellar hydrogel (AF127/HA-ADH/OHA-Dop) with outstanding adhesive and self-healing properties able to accelerate full-thickness skin wound healing. Dopamine-functionalized oxidized hyaluronic acid (OHA-Dop), adipic acid dihydrazide-modified HA (HA-ADH), and aldehyde-terminated Pluronic F127 (AF127) were employed as polymer backbones. They were cross-linked in situ using Schiff base dynamic covalent bonds (AF127 micelle/HA-ADH network and HA-ADH/OHA-Dop network), hydrogen bonding, and π-π stacking interactions. The resulting multicross-linked double-network design forms a micellar hydrogel. The unique multicross-linked double-network structure endows the hydrogel with both improved injection abilities and mechanical performance while self-healing faster than single-network hydrogels. Inspired by mussel foot adhesive protein, OHA-Dop mimics the catechol groups seen in mussel proteins, endowing hydrogels with robust adhesion properties. We also demonstrate the potential of our hydrogels to accelerate full-thickness cutaneous wound closure and improve skin regeneration with reduced scarring. We anticipate that our hydrogel platform based on a novel multicross-linked double-network design will transform the future development of multifunctional wound dressings.

3D bioprinting has been developed as a promising technology in a wide variety of biomedical applications. However, the successful implementation of bioprinting is still heavily restricted by the relatively narrow range of printable and biocompatible materials. Recently, many comprehensive reviews of the main bioprinting methods, commonly used bioprinting materials and the trending bioprinting applications have been carried out. In this review, we focused on the trends in the development of materials for 3D bioprinting. The significance and recent advances of ECM-based materials, multi-material and stimuli-responsive materials for bioprinting were summarized successively. Moreover, the challenges in current studies and future perspectives of materials for 3D bioprinting were discussed.

Multiple sclerosis (MS) is a neurological disorder characterized by loss of the myelin sheath. Since the myelin sheath could insulate nerve fibers from the surrounding environment, its loss would result in dysfunction of the affected neurons in transmitting electrical signals, thus leading to sensation and motor disabilities. The treatment of MS is accompanied by a low treatment efficacy due to the existence of the blood-brain barrier (BBB) and occurrence of side effects due to a poor targeting efficacy. To overcome these obstacles of traditional MS treatment methods, nanomedicines have recently been employed to deliver MS therapeutic agents to the lesions. With deep BBB penetration and specific targeting, these nano-based interventions have received positively encouraging results and become another potential MS treatment method with better therapeutic outcomes. This review will focus on recent advances in nanomedicines for the treatment of MS by critically analyzing their strengths and weaknesses. We will propose perspectives on the development of these MS therapeutic nanomaterials.

In recent years, with the emergence of various kinds of drug-resistant bacteria, existing antibiotics have become inefficient in killing these bacteria, and the formation of biofilms has further weakened the therapeutic effect. More problematically, the massive use and abuse of antibiotics have caused severe side effects. Thus, the development of ultra-efficient and safe antibacterial systems is urgently needed. Herein, a photodynamic therapy (PDT)-driven CO-controlled delivery system (Ce6&CO@FADP) is developed for synergistic antibacterial and ablation biofilms. Ce6&CO@FADP is constructed using a fluorinated amphiphilic dendritic peptide (FADP) and physically loaded with Ce6 and CORM-401. After efficiently entering the bacteria, Ce6&CO@FADP can rapidly release CO intracellularly by the massive consumption of the H2O2 generated during the PDT process, without affecting the generation of singlet oxygen (1O2). As such, the combination of CO and 1O2 exerts notable synergistic antibacterial and biofilm ablation effects both in vitro and in vivo (including subcutaneous bacterial infection and biofilm catheter models) experiments. More importantly, all biosafety assessments suggest the good biocompatibility of Ce6&CO@FADP. Together, these results reveal that Ce6&CO@FADP is an efficient and safe antibacterial system, which has essential application prospects for the treatment of bacterial infections and ablation of biofilms in vivo.

Rapid development of stimuli-responsive drug delivery systems (DDSs) for tumor therapy has raised increasing interest in recent decades, and many nanomedicines are prepared to achieve accurate or sustained drug release. However, the fabrication process for these nanomedicines has been far too intricate and their potential biosafety has not been fully understood, which has hampered their clinical translation. Challenges for developing DDSs remain on balancing the complexity of the fabrication process with their translational feasibility. Owing to water-solubility, biocompatibility, biodegradability and CD44-targetability, hyaluronic acid (HA) as a versatile building block has gained great popularity due to a simplified fabrication process and unique characteristics of HA for DDSs. In this review, we overviewed the biological function and multiple chemical modifications of HA, and discussed the fabrication of HA-based drug delivery systems (HA-DDSs) with specific tumor microenvironmental stimuli-responsive linkers. We systemically surveyed the applications of HA-DDSs for chemotherapy, photothermal therapy, photodynamic therapy, immunotherapy, gene delivery and combination therapy.

Combination therapy is a promising approach for effective treatment of tumors through synergistically regulating pathways. However, the synergistic effect is limited, likely by uncontrolled co-delivery of different therapeutic payloads in a single nanoparticle. Herein, a combination nanotherapeutic is developed by using two amphiphilic conjugates, hyperbranched poly(ethylene glycol)-pyropheophorbide-a (Ppa) (HP-P) and hyperbranched poly(ethylene glycol)-doxorubicin (DOX) (HP-D) to construct co-assembly nanoparticles (HP-PD NPs) for controllably co-loading and co-delivering Ppa and DOX. In vitro and in vivo antitumor studies confirm the synergistic effect of photodynamic therapy and chemotherapy from HP-PD NPs. Metabolic variations reveal that tumor suppression is associated with disruption of metabolic homeostasis, leading to reduced protein translation. This study uncovers the manipulation of metabolic changes in tumor cells through disruption of cellular homeostasis using HP-PD NPs and provides a new insight into the rational design of synergistic nanotherapeutics for combination therapy.

Linear-dendritic block copolymer (LDBCs) are highly attractive candidates for smart drug delivery vehicles. Herein, we report an amphiphilic poly[(ethylene glycol) methyl ether methacrylate] (POEGMA) linear-peptide dendritic prodrug of doxorubicin (DOX) prepared by reversible addition-fragmentation chain transfer (RAFT) polymerization. A hydrophobic dye-based photosensitizer chlorin e6 (Ce6) was employed for encapsulation in the prodrug nanoparticles (NPs) to obtain a LDBCs-based drug delivery system (LD-DOX/Ce6) which offered a combination cancer therapy. Due to the presence of Gly-Phe-Leu-Gly peptides and hydrazone bonds in the prodrug structure, LD-DOX/Ce6 were degraded into small fragments, thus specifically triggering the intracellular release of DOX and Ce6 in the tumor microenvironment. Bioinformatics analysis suggested that LD-DOX/Ce6 with laser irradiation treatment significantly induced apoptosis, DNA damage and cell cycle arrest. The combination treatment could not only suppress tumor growth, but also significantly reduced tumor metastasis compared with treatments with DOX or Ce6 through regulating EMT pathway, TGFβ pathway, angiogenesis and the hypoxia pathway. LD-DOX/Ce6 displayed a synergistic chemo-photodynamic anti-tumor efficacy, resulting in a high inhibition in tumor growth and metastasis, while maintaining an excellent biosafety. Therefore, this study has demonstrated potential of the biodegradable and tumor microenvironment-responsive LDBCs as an intelligent multifunctional drug delivery vehicle for high-efficiency cancer combination therapy. This article is protected by copyright. All rights reserved.

Hydrogel tissue adhesives that currently available are often fabricated by mixing two or more polymeric components. Single-component hydrogels afford injectability, strong and reversible adhesion remain a formidable challenge. This research describes the creation of the first single-component hyaluronic acid hydrogel adhesive-based on phenylboronic acid-diol ester linkages. Phenylboronic acid can not only serve as a cross-linker to form hydrogel, but also act as an adhesion site for glycosyl compounds found in biological cell membranes. The rheological and compressive tests for the hydrogel show that it has excellent self-healing properties, good injectability and strong compressive strength. Adhesion tests demonstrated that the hydrogel has significantly greater adhesion strength than commercial fibrin glue. These findings suggest that the rational design of hydrogel precursors facilitates the formation of single-component networks and multiple functionalities. In vivo studies further proved the hydrogel was an ideal bio-adhesive with biocompatibility, absorbed wound exudate and hemostasis, and accelerated wound closure.

Photocrosslinked hydrogels show great potential as dressings for skin wound healing. However, most current hydrogels suffer from poor adhesion, toxic photoinitiators, and insufficient versatility. Therefore, developing novel hydrogel dressings with appropriate properties is of great importance to accelerate the wound healing process. In this study, we developed a polysaccharide-based dual-network hydrogel consisting of azide-functionalized carboxymethyl chitosan and o-nitrobenzyl-modified hyaluronic acid (CMC-AZ/HA-NB). The hydrogel showed excellent mechanical, tissue adhesion, and water retention properties. Controllable in situ photocrosslinking was carried out without photoinitiator, avoiding issues associated with the cytotoxicity of photoinitiators. An antibacterial agent-loaded hydrogel (CMC-AZ/HA-NB@D) showed enhanced antibacterial properties. In addition, the CMC-AZ/HA-NB@D hydrogel promoted collagen deposition and vascular formation, as well as reducing the expression of pro-inflammatory factors, thereby accelerating the wound healing process and improving skin regeneration. The present results highlight the promising potential of multifunctional photoinitiator-free polysaccharide hydrogels for application in wound dressings.

Disulfiram (DSF) has been used as an alcoholism drug for 70 years. Recently, it has attracted increasing attention owing to the distinguished anticancer activity, which can be further potentiated by the supplementation of Cu

Magnetic resonance (MR) contrast agents have been explored to improve the diagnosis of vascular diseases or tumors, yet clinically used small molecular agents have not been very successful owing to their poor contrast efficiency and short circulation time. Herein we reported a biodegradable HPMA polymeric micelle-based MR contrast agent containing gadolinium (Gd3+) for imaging murine vascular structures and tumors. This nano-sized polymeric agent has a high relaxivity, good biosafety and great biodegradability for MR applications. In vivo MR angiography (MRA) clearly reveals the abdominal, intracranial and tumor-surrounding blood vessels for a longer time after injection of the polymeric agent compared to DTPA-Gd. Furthermore, orthotopic and subcutaneous imaging of a murine breast cancer tumor model demonstrates that this polymeric agent has excellent contrast enhancement in tumors. The enhancement may be due to great accumulation of the polymeric agent in tumors and tumor associated macrophages (TAM) might help improve the accumulation of the polymeric agent in tumors. Thus, in comparison with DTPA-Gd, this polymeric micelle-based biodegradable and biocompatible contrast agent has been demonstrated to have a high MRI contrast efficacy for murine vasculatures and tumors.

Hepatic fibrosis is induced by chronic hepatic injuries before it turns into hepatic cirrhosis/carcinoma. It is characterized by the formation of collagen and other extracellular matrices around damaged hepatic tissues; consequently, the normal architecture of liver would be disrupted and its function impaired. Diagnosis of hepatic fibrosis, especially at the early stage, is crucial because most fibrotic changes are reversible during the hepatic fibrosis stage. However, early and more accurate diagnosis of hepatic fibrosis still remains a great challenge. With their promising structural adjustability and targeting ability, nanomedicines have recently been introduced to improve diagnosis of hepatic fibrosis. By targeting fibrogenic cells, receptors, and extracellular matrix components, these nanomedicines can achieve detection of hepatic tissues with high sensitivity and specificity at the early stage. The use of nanomedicines can also enable theranostics of this chronic hepatic disease. This review aims to present an overview of recent advances of nanomedicines in diagnosis and theranostics of hepatic fibrosis.

Patient-derived xenograft (PDX) models are powerful tools for understanding cancer biology and drug discovery. In this study, a polymeric nano-sized drug delivery system poly (OEGMA)-PTX@Ce6 (NPs@Ce6) composed of a photosensitizer chlorin e6 (Ce6) and a cathepsin B-sensitive polymer-paclitaxel (PTX) prodrug was constructed. The photochemical internalization (PCI) effect and enhanced chemo-photodynamic therapy (PDT) were achieved via a two-stage light irradiation strategy. The results showed that the NPs@Ce6 had great tumor targeting and rapid cellular uptake induced by PCI, thereby producing excellent anti-tumor effects on human bladder cancer PDX models with tumor growth inhibition greater than 98%. Bioinformatics analysis revealed that the combination of PTX chemotherapy and PDT up-regulated oxidative phosphorylation and reactive oxygen species (ROS) generation, blocked cell cycle and proliferation, and down-regulated the pathways related to tumor progression, invasion and metastasis, including hypoxia, TGF-β signaling and TNF-α signaling pathways. Western blots analysis confirmed that proteins promoting apoptosis (Bax, Cleaved caspase-3, Cleaved PARP) and DNA damage (γH2A.X) were up-regulated, while those inhibiting apoptosis (Bcl-2) and mitosis (pan-actin and α/β-tubulin) were down-regulated after chemo-PDT treatment. Therefore, this stimuli-responsive polymer-PTX prodrug-based nanomedicine with combinational chemotherapy and PDT evaluated in the PDX models could be a potential candidate for bladder cancer therapy.

Regulating the secretion and endothelial differentiation of human mesenchymal stem cells (hMSCs) plays an important role in the vascularization in tissue engineering and regenerative medicine. In this study, a recombinant cadherin fusion protein consisting of a human vascular endothelial-cadherin extracellular domain and immunoglobulin IgG Fc region (hVE-cad-Fc) was developed as a bioartificial matrix for modulating hMSCs. The hVE-cad-Fc matrix significantly enhanced the secretion of angiogenic factors, activated the VE-cadherin-VEGFR2/FAK-AKT/PI3K signaling pathway in hMSCs, and promoted the endothelial differentiation of hMSCs even without extra VEGF. Furthermore, the hVE-cad-Fc matrix was applied for the surface modification of a poly (lactic-co-glycolic acid) (PLGA) porous scaffold, which significantly improved the hemocompatibility and vascularization of the PLGA scaffold in vivo. These results revealed that the hVE-cad-Fc matrix should be a superior bioartificial ECM for remodeling the pro-vascularization extracellular microenvironment by regulating the secretion of hMSCs, and showed great potential for the vascularization in tissue engineering.

An amphiphilic peptide dendrimer conjugated with gemcitabine (GEM), PEGylated dendron-Gly-Phe-Leu-Gly-GEM (PEGylated dendron-GFLG-GEM), is developed as a nano-prodrug for breast cancer therapy. The self-assembled behavior is observed under a transmission electron microscopy and dynamic light scattering. The negatively charged surface and hydrodynamic size of the amphiphilic nanosized prodrug supported that the prodrug can maintain the stability of GEM during circulation and accumulate in the tumor tissue. Drug release assays are conducted to monitor the release of GEM from this nanodrug delivery system in response to the tumor microenvironment, and these assays confirm that GEM released from the nanocarrier is identical to free GEM. The GEM prodrug can prevent proliferation of tumor cells. The therapeutic effect against breast cancer is systematically investigated using an in vivo animal model. Immunohistochemical results are aligned with the significantly enhanced anticancer efficacy of GEM released from the prodrug. This self-assembled amphiphilic drug delivery nanocarrier may broaden the application for GEM and other anticancer agents for breast cancer chemotherapy.

Combinatorial short interference RNA (siRNA) technology for the silencing of multiple genes is expected to provide an effective therapeutic approach for cancer with complex genetic mutation and dysregulation. Herein we present a tumor-activatable supramolecular nanoplatform for the delivery of siRNAs to target telomerase and telomeres for paclitaxel-resistant non-small-cell lung cancer (A549/PTX) treatment. Two different sequences of siRNA are incorporated in a single nanoparticle, which is obtained by self-assembly from a peptide dendrimer. The siRNA stability is improved by the nanoparticle in the presence of serum compared to free siRNA, and these siRNAs are protected from RNA enzyme degradation. In the tumor extracellular acid environment, the PEG corona of the nanoparticle is removed to promote the internalization of siRNAs into tumor cells. The disulfide linkages between the nanoparticle and siRNAs are cleared in the reductive environment of the tumor cells, and the siRNAs are released in the cytoplasm. In vitro experiments show that the gene expression of hTERT and TRF2 at the mRNA and protein levels of A549/PTX tumor cells is down-regulated, which results in cooperative restraining proliferation and invasion of A549/PTX tumor cells. For the tumor cell-targeting function of the MUC1 aptamer and the EPR effect, sufficient tumor accumulation of nanoparticles was observed. Meanwhile, a shift of negative surface charge of nanoparticles to positive charge in the tumor extracellular microenvironment enhances deep penetration of siRNA-incorporating nanoparticles into tumor tissues. In vivo animal studies support that successful down-regulation of hTERT and TRF2 gene expression achieves effective inhibition of the growth and neovascularization of drug-resistant tumor cells. This work has provided a new avenue for drug-resistant cancer treatment by designing and synthesizing a tumor-activatable nanoplatform to achieve the delivery of dual-gene targeted combinatorial siRNAs.

Morphology genetic biomedical materials (MGBMs), referring to fabricating materials by learning from the genetic morphologies and strategies of natural species, hold great potential for biomedical applications. Inspired by the cargo-carrying-bacterial therapy (microbots) for cancer treatment, a MGBM (artificial microbots, AMBs) was constructed. Rather than the inherent bacterial properties (cancerous chemotaxis, tumor invasion, cytotoxicity), AMBs also possessed ingenious nitric oxide (NO) generation strategy. Mimicking the bacterial construction, the hyaluronic acid (HA) polysaccharide was induced as a coating capsule of AMBs to achieve long circulation in blood and specific tissue preference (tumor tropism). Covered under the capsule-like polysaccharide was the combinatorial agent, the self-assembly constructed by the amphiphilic dendrons with abundant l-arginine residues peripherally (as endogenous NO donor) and hydrophobic chemotherapeutic drugs at the core stacking on the surface of SWNTs (the photothermal agent) for a robust chemo-photothermal therapy (chemo-PTT) and the elicited immune therapy. Subsequently, the classic inducible nitric oxide synthase (iNOS) pathway aroused by immune response was revolutionarily utilized to oxidize the l-arginine substrates for NO production, the process for which could also be promoted by the high reactive oxygen species level generated by chemo-PTT. The NO generated by AMBs was intended to regulate vasodilation and cause a dramatic invasion (as the microbots) to disperse the therapeutic agents throughout the solid tumor for a much more enhanced curative effect, which we defined as "self-propulsion". The self-propelled AMBs exhibiting impressive primary tumor ablation, as well as the distant metastasis regression to conquer the metastatic triple negative breast cancer, provided pioneering potential therapeutic opportunities, and enlightened broad prospects in biomedical application.

Precisely delivering combinational therapeutic agents has become a crucial challenge for anti-tumor treatment. In this study, a novel redox-responsive polymeric prodrug (molecular weight, MW: 93.5 kDa) was produced by reversible addition–fragmentation chain transfer (RAFT) polymerization. The amphiphilic block polymer-doxorubicin (DOX) prodrug was employed to deliver a hydrophobic photosensitizer (PS), chlorin e6 (Ce6), and the as-prepared nanoscale system [NPs(Ce6)] was investigated as a chemo-photodynamic anti-cancer agent. The glutathione (GSH)-cleavable disulfide bond was inserted into the backbone of the polymer for biodegradation inside tumor cells, and DOX conjugated onto the polymer with a disulfide bond was successfully released intracellularly. NPs(Ce6) released DOX and Ce6 with their original molecular structures and degraded into segments with low MWs of 41.2 kDa in the presence of GSH. NPs(Ce6) showed a chemo-photodynamic therapeutic effect to kill 4T1 murine breast cancer cells, which was confirmed from a collapsed cell morphology, a lifted level in the intracellular reactive oxygen species, a reduced viability and induced apoptosis. Moreover, ex vivo fluorescence images indicated that NPs(Ce6) retained in the tumor, and exhibited a remarkable in vivo anticancer efficacy. The combinational therapy showed a significantly increased tumor growth inhibition (TGI, 58.53%). Therefore, the redox-responsive, amphiphilic block polymeric prodrug could have a great potential as a chemo-photodynamic anti-cancer agent., Graphical abstract An amphiphilic and block polymer–doxorubicin prodrug was prepared, and employed as the stimuli-responsive micelles to load chlorin e6. Anticancer mechanism was studied showing great potential as a chemo-photodynamic anti-cancer agent.Image 1

Tumor immunotherapy is only effective in a fraction of patients due to a low response rate and severe side effects, and these challenges of immunotherapy in clinics can be addressed through induction of immunogenic cell death (ICD). ICD is elicited from many antitumor therapies to release danger associated molecular patterns (DAMPs) and tumor-associated antigens to facilitate maturation of dendritic cells (DCs) and infiltration of cytotoxic T lymphocytes (CTLs). The process can reverse the tumor immunosuppressive microenvironment to improve the sensitivity of immunotherapy. Nanostructure-based drug delivery systems (NDDSs) are explored to induce ICD by incorporating therapeutic molecules for chemotherapy, photosensitizers (PSs) for photodynamic therapy (PDT), photothermal conversion agents for photothermal therapy (PTT), and radiosensitizers for radiotherapy (RT). These NDDSs can release loaded agents at a right dose in the right place at the right time, resulting in greater effectiveness and lower toxicity. Immunotherapeutic agents can also be combined with these NDDSs to achieve the synergic antitumor effect in a multi-modality therapeutic approach. In this review, NDDSs are harnessed to load multiple agents to induce ICD by chemotherapy, PDT, PTT, and RT in combination of immunotherapy to promote the therapeutic effect and reduce side effects associated with cancer treatment.

Additional file 1: Fig. S1. 1H NMR spectrum (400 MHz) of mPEG-LA conjugates in CDCl3. Fig. S2. SEM image (A), size (B) and zeta potential (C) of the self-assembly of mPEG-LA conjugates (NPs, 100 g mL−1). Fig. S3. Size distribution of MPNs at different concentrations. Fig. S4. Fluorescence spectra of a mixed solution of NPs (100 μg mL−1)and MPNs (100 μg mL−1) prepared with 0.1 wt% DiO/DiI tracing the development of FRET between two dyes. Fig. S5. Critical aggregation concentration of MPNs at (A) pH 7.4 or (B) 6.5. Fig. S6. Fluorescence spectra of a mixed solution of MPNs (100 μg mL−1, pH 6.5) prepared with 0.1 wt% DiO/DiI tracing the development of FRET between two dyes over time. Fig. S7. Flow cytometric histogram profiles of 4T1 cells treated with MPNs, DOX, D-NPs and D-MPNs for 3 h (DOX concentration: 10 μg mL−1). Fig. S8. CLSM images of 4T1 cells incubated with DOX, D-NPs, D-MPNs and DOX·HCl for 1 h (DOX dosage: 2 μg mL−1). Hoechst 33342 was used to stain the cell nuclei. Scale bar: 10 μm. Fig. S9. Quantitative assessment of penetration of DOX formulations into 4T1 cells. The cells were incubated with DOX, D-NPs and D-MPNs at a DOX concentration of 5 μg mL−1 for 2 h. Fig. S10. IOD (Integrated optical density) of immunohistochemical images for saline, MPNs, DOX·HCl, D-NPs and D-MPNs groups. The apoptotic rates of tumor sections based on TUNEL images (A), tumor microvessel density based on CD31 images (B) and Ki67 positive cells (C) of tumor sections were calculated with Image-Pro Plus 6.0 software. Data were presented as mean ± SD (n = 3), *p < 0.01, **p < 0.005. Fig. S11. Body weight changes of 4T1-bearing BALB/c mice after administration with saline, MPNs, DOX·HCl, D-NPs and D-MPNs (n = 8, dosage: 5 mg DOX kg−1 mouse body weight, *p < 0.01). The arrows indicated the time points for intravenous injection. Fig. S12. Routine blood analysis results of the mice collected on the 12th day after intravenous injection of saline, MPNs, DOX·HCl, D-NPs or D-MPNs. The results show mean and standard deviation of white blood cells (WBCs), red blood cell (RBC), hemoglobin (HGB) and platelets (PLT). Fig. S13. Histological examination of major organs separated from 4T1-bearing BALB/c mice after administration with saline, MPNs, DOX·HCl, D-NPs and D-MPNs for 18 days. Scale bar: 100 μm. Fig. S14. TUNEL staining of heart (×200) of 4T1-bearing BALB/c mice after administration with saline, MPNs, DOX·HCl, D-NPs and D-MPNs for 18 days. The apoptotic cells (red arrow) and normal cells were stained brown and blue, respectively. Table S1. Pharmacokinetic parameters of DOX·HCl, D-NPs and D-MPNs after intravenous administration at an equivalent dose of 10 mg DOX/kg mouse body weight (n = 3 per group).

Smart MICE has been increasingly applied to describe the integration of technologies into Meetings, Incentive Travels, Conventions/Conferences and Exhibitions (MICE) industry. However, Smart MICE lacks definitional clarity and the understanding of its theoretical foundation is unclear. This paper aims to provide a clarified definition, and analyze technological and business foundations for Smart MICE. Among similar concepts, MICE informatization is the adoption and application process of management information systems. Online MICE is the combination of online conference and online exhibition. Smart MICE is an upgrade and logical progression of MICE industry. Based on literature reviews, three tiers of Smart MICE are high-tech service industry, smart experience enhancement and complex business network. Technologies in Smart MICE are applied for infrastructure and framework, feedback and experience, and identifying and tracking. Value proposition and components of partners are key factors in Smart MICE business model. Technological and business foundations are analyzed to gain a better perspective of Smart MICE. Future areas of research agendas are discussed to facilitate the development of Smart MICE.

Hypoxia and hypoxia induced overexpression of vascular endothelial growth factor (VEGF) not only seriously affects the treatment effects of photodynamic therapy (PDT) but also promotes tumor metastasis. Herein, an alternating irradiation strategy (referred to as alternate use of low/high dose of light [ALHDL] irradiation)-driven combination therapy of PDT and RNA interference (RNAi) is developed to synergistically inhibit tumor growth and metastasis. A cationic amphipathic peptide (ALS) served as a carrier in the co-delivery system of photochlor (HPPH) and siVEGF (ALSH/siVEGF). At the beginning of ALHDL-driven ALSH/siVEGF treatment, short-term LDL irradiation can facilitate the tumor penetration, cellular uptake, and endosome escape of ALSH/siVEGF. Moreover, accompanied by HDL-mediated rapid cell apoptosis and LDL-mediated efficient VEGF silencing, the joint use of PDT and RNAi achieved remarkable antitumor effects both in vitro and in vivo. Importantly, benefited from the excellent performance of ALHDL in slowing the rapid deterioration of the anoxic environment of tumors, and ALSH/siVEGF treatment-mediated highly improved VEGF silencing efficacy and inhibitory effect on angiogenesis, the liver and lung metastases of HeLa cells have been successfully suppressed. Together, this study clearly indicates that ALHDL-driven combination therapy of PDT and RNAi is a highly effective modality for inhibition of tumor growth and metastasis.

Effective wound dressings are of great significance in preventing infections and promoting wound healing. However, most existing hydrogel dressings have an inadequacy in either mechanical performance, biological activities, or versatilities. Here we presented a double-network cross-linked polysaccharide-based hydrogel composed of collagen peptide-functionalized carboxymethyl chitosan (CS) and oxidized methacrylate sodium alginate (SA). The hydrogel possessed interconnected porous morphologies, suitable swelling ratios, excellent mechanical properties, and favorable biocompatibility. Meanwhile, the in vivo studies using a mouse full-thickness skin defect model showed that the double-network CS/SA hydrogel significantly accelerated wound healing by regulating the inflammatory process, promoting collagen deposition, and improving vascularization. Therefore, the functionalized double-network hydrogel should be a potential candidate as wound dressings.