Shape memory polymer with programmable recovery onset.

Stimulus-responsive shape-shifting polymers1-3 have shown unique promise in emerging applications, including soft robotics4-7, medical devices8, aerospace structures9 and flexible electronics10. Their externally triggered shape-shifting behaviour offers on-demand controllability essential for many device applications. Ironically, accessing external triggers (for example, heating or light) under realistic scenarios has become the greatest bottleneck in demanding applications such as implantable medical devices8. Certain shape-shifting polymers rely on naturally present stimuli (for example, human body temperature for implantable devices)8 as triggers. Although they forgo the need for external stimulation, the ability to control recovery onset is also lost. Naturally triggered, yet actively controllable, shape-shifting behaviour is highly desirable but these two attributes are conflicting. Here we achieved this goal with a four-dimensional printable shape memory hydrogel that operates via phase separation, with its shape-shifting kinetics dominated by internal mass diffusion rather than by heat transport used for common shape memory polymers8-11. This hydrogel can undergo shape transformation at natural ambient temperature, critically with a recovery onset delay. This delay is programmable by altering the degree of phase separation during device programming, which offers a unique mechanism for shape-shifting control. Our naturally triggered shape memory polymer with a tunable recovery onset markedly lowers the barrier for device implementation.

Tumor Abnormality-Oriented Nanomedicine Design.

Anticancer nanomedicines have been proven effective in mitigating the side effects of chemotherapeutic drugs. However, challenges remain in augmenting their therapeutic efficacy. Nanomedicines responsive to the pathological abnormalities in the tumor microenvironment (TME) are expected to overcome the biological limitations of conventional nanomedicines, enhance the therapeutic efficacies, and further reduce the side effects. This Review aims to quantitate the various pathological abnormalities in the TME, which may serve as unique endogenous stimuli for the design of stimuli-responsive nanomedicines, and to provide a broad and objective perspective on the current understanding of stimuli-responsive nanomedicines for cancer treatment. We dissect the typical transport process and barriers of cancer drug delivery, highlight the key design principles of stimuli-responsive nanomedicines designed to tackle the series of barriers in the typical drug delivery process, and discuss the "all-into-one" and "one-for-all" strategies for integrating the needed properties for nanomedicines. Ultimately, we provide insight into the challenges and future perspectives toward the clinical translation of stimuli-responsive nanomedicines.

Alkylated EDTA potentiates antibacterial photodynamic activity of protoporphyrin.

Antibiotic resistance has garnered significant attention due to the scarcity of new antibiotics in development. Protoporphyrin IX (PpIX)-mediated photodynamic therapy shows promise as a novel antibacterial strategy, serving as an alternative to antibiotics. However, the poor solubility of PpIX and its tendency to aggregate greatly hinder its photodynamic efficacy. In this study, we demonstrate that alkylated EDTA derivatives (aEDTA), particularly C14-EDTA, can enhance the solubility of PpIX by facilitating its dispersion in aqueous solutions. The combination of C14-EDTA and PpIX exhibits potent antibacterial activity against Staphylococcus aureus (S. aureus) when exposed to LED light irradiation. Furthermore, this combination effectively eradicates S. aureus biofilms, which are known to be strongly resistant to antibiotics, and demonstrates high therapeutic efficacy in an animal model of infected ulcers. Mechanistic studies reveal that C14-EDTA can disrupt PpIX crystallization, increase bacterial membrane permeability and sequester divalent cations, thereby improving the accumulation of PpIX in bacteria. This, in turn, enhances reactive oxygen species (ROS) production and the antibacterial photodynamic activity. Overall, this effective strategy holds great promise in combating antibiotic-resistant strains.

Role of Micelle Size in Cell Transcytosis-Based Tumor Extravasation, Infiltration, and Treatment Efficacy.

Transcytosis-based active transport of cancer nanomedicine has shown great promise for enhancing its tumor extravasation and infiltration and antitumor activity, but how the key nanoproperties of nanomedicine, particularly particle size, influence the transcytosis remains unknown. Herein, we used a transcytosis-inducing polymer, poly[2-(N-oxide-N,N-diethylamino)ethyl methacrylate] (OPDEA), and fabricated stable OPDEA-based micelles with different sizes (30, 70, and 140 nm in diameter) from its amphiphilic block copolymer, OPDEA-block-polystyrene (OPDEA-PS). The study of the micelle size effects on cell transcytosis, tumor extravasation, and infiltration showed that the smallest micelles (30 nm) had the fastest transcytosis and, thus, the most efficient tumor extravasation and infiltration. So, the 7-ethyl-10-hydroxyl camptothecin (SN38)-conjugated OPDEA micelles of 30 nm had much enhanced antitumor activity compared with the 140 nm micelles. These results are instructive for the design of active cancer nanomedicine.

Multifunctional Nanoassembly for MRI-Trackable Dendritic Cell Dependent and Independent Photoimmunotherapy.

Immunotherapy has emerged as a triumph in the treatment of malignant cancers. Nevertheless, current immunotherapeutics are insufficient in addressing tumors characterized by tumor cells' inadequate antigenicity and the tumor microenvironment's low immunogenicity (TME). Herein, we developed a novel multifunctional nanoassembly termed FMMC through the self-assembly of indoleamine 2,3-dioxygenase 1 (IDO-1) inhibitor 1-methyl-tryptophan prodrug (FM), Ce6, and ionic manganese (Mn2+) via noncovalent interactions. The laser-ignited FMMC treatment could induce effective immunogenic cell death and activate the STING/MHC-I signaling pathway, thus deeply sculpting the tumor-intrinsic antigenicity to achieve dendritic cell (DC)-dependent and -independent T cell responses against tumors. Meanwhile, by inhibiting IDO-1, FMMC could lead to immunosuppressive TME reversion to an immunoactivated one. FMMC-based phototherapy led to the up-regulation of programmed death-ligand 1 (PD-L1), enhancing the sensitivity of tumors to anti-PD-1 therapy. Furthermore, the incorporation of Mn2+ into FMMC resulted in an augmented longitudinal relaxivity and enhanced the MRI for monitoring the growth of primary tumors and lung metastases. Collectively, the superior reprogramming performance of immunosuppressive tumor cells and TME, combined with excellent anticancer efficacy and MRI capability, made FMMC a promising immune nanosculptor for cancer theranostics.

Peritoneal Gene Transfection of Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand for Tumor Surveillance and Prophylaxis.

Peritoneal metastasis is very common in gastrointestinal, reproductive, and genitourinary tract cancers in late stages or postsurgery, causing poor prognosis, so effective and nontoxic prophylactic strategies against peritoneal metastasis are highly imperative. Herein, we demonstrate the first gene transfection as a nontoxic prophylaxis preventing peritoneal metastasis or operative metastatic dissemination. Lipopolyplexes of TNF-related-apoptosis-inducing-ligand (TRAIL) transfected peritonea and macrophages to express TRAIL for over 15 days. The expressed TRAIL selectively induced tumor cell apoptosis while exempting normal tissue, providing long-term tumor surveillance. Therefore, tumor cells inoculated in the pretransfected peritoneal cavity quickly underwent apoptosis and, thus, barely formed tumor nodules, significantly prolonging the mouse survival time compared with chemotherapy prophylaxis. Furthermore, lipopolyplex transfection showed no sign of toxicity. Therefore, this peritoneal TRAIL-transfection is an effective and safe prophylaxis, preventing peritoneal metastasis.

Highly Sensitive Imaging of Tumor Metastasis Based on the Targeting and Polarization of M2-like Macrophages.

Tumor-associated macrophages, especially M2-like macrophages, are extensively involved in tumor growth and metastasis, suppressing the innate immunity to help tumor cells escape and reshaping the microenvironment to help metastatic cells grow. However, in vivo, real-time visualized migration of M2-like macrophages has never been explored to monitor the tumor metastasis process. Herein, we prepared an M2-like macrophage-targeting nitric oxide (NO)-responsive nanoprobe (NRP@M-PHCQ) consisting of an amphiphilic block copolymer with mannose and hydroxychloroquine (HCQ) moieties (denoted as M-PHCQ) and a NO-responsive NIR-II probe (denoted as NRP). The mannose moieties provided M2-like macrophage-targeting capacity, and the HCQ moieties polarized M2-like macrophages to M1-like ones with enhanced NO secretion. Consequently, NRP@M-PHCQ was lit up by the secreted NO to visualize the migration and polarization of M2-like macrophages in real time. In vivo metastasis imaging with NRP@M-PHCQ successfully tracked early tumor metastasis in the lymph nodes and the lungs with high sensitivity, even superior to Luci-labeled bioluminescence imaging, suggesting the extensive distribution and critical role of M2-like macrophages in tumor metastasis. In general, this work provided a new strategy to sensitively image metastatic tumors by tracking the polarization of M2-like macrophages and visually disclosed the critical role of M2-like macrophages in early tumor metastasis.

Research Status of Dendrimer Micelles in Tumor Therapy for Drug Delivery.

Dendrimers are a family of polymers with highly branched structure, well-defined composition, and extensive functional groups, which have attracted great attention in biomedical applications. Micelles formed by dendrimers are ideal nanocarriers for delivering anticancer agents due to the explicit study of their characteristics of particle size, charge, and biological properties such as toxicity, blood circulation time, biodistribution, and cellular internalization. Here, the classification, preparation, and structure of dendrimer micelles are reviewed, and the specific functional groups modified on the surface of dendrimers for tumor active targeting, stimuli-responsive drug release, reduced toxicity, and prolonged blood circulation time are discussed. In addition, their applications are summarized as various platforms for biomedical applications related to cancer therapy including drug delivery, gene transfection, nano-contrast for imaging, and combined therapy. Other applications such as tissue engineering and biosensor are also involved. Finally, the possible challenges and perspectives of dendrimer micelles for their further applications are discussed.

Yolk-shell Co3 O4 @Fe3 O4 /C Nanocomposites as a Heterogeneous Fenton-like Catalyst for Organic Dye Removal.

The yolk-shell Co3 O4 @Fe3 O4 /C nanocomposites with Co3 O4 as the core, Fe3 O4 /C as the shell, and a cavity structure were synthesized by the hard template method. The physical and chemical properties of the composites were characterized by SEM, TEM, XRD, TGA, XPS, BET, and VSM. The specific surface area of yolk-shell Co3 O4 @Fe3 O4 /C nanocomposites is 175.9 m2  g-1 , showing superparamagnetic properties. The yolk-shell Co3 O4 @Fe3 O4 /C nanocomposites were used as heterogeneous Fenton catalysts to activate peroxymonosulfate (PMS) to degrade MB, which showed high catalytic degradation performance. The degradation rate of MB reached 100 % within 30 min under the circumstances of the yolk-shell Co3 O4 @Fe3 O4 /C nanocomposites dosage of 0.1 g L-1 , the PMS dosage of 1.0 g L-1 , the initial MB concentration of 100 mg L-1 , an initial pH of 5.5, and a temperature of 30±2 °C. The enhanced catalytic performance of the yolk-shell Co3 O4 @Fe3 O4 /C nanocomposites can be attributed to the synergistic effect of the two catalytically active materials and the middle cavity. The effects of different operating parameters and co-existing anion species on MB degradation were also investigated. Electron paramagnetic resonance (EPR) analysis and quenching experiments confirmed that the formation of SO4 ⋅- in the yolk-shell Co3 O4 @Fe3 O4 /C/PMS system contributes to MB degradation. In addition, yolk-shell Co3 O4 @Fe3 O4 /C nanocomposites can be easily separated from the pollutant solution under the action of an external magnetic field, and the degradation rate of MB can still reach 98 % after five cycles, indicating that it has good stability and reusability and has broad application prospects in the field of water purification.

Recent development and application of membrane chromatography.

Membrane chromatography is mainly used for the separation and purification of proteins and biological macromolecules in the downstream processing process, also applications in sewage disposal. Membrane chromatography is recognized as an effective alternative to column chromatography because it significantly improves chromatography from affinity, hydrophobicity, and ion exchange; the development status of membrane chromatography in membrane matrix and membrane equipment is thoroughly discussed, and the applications of protein capture and intermediate purification, virus, monoclonal antibody purification, water treatment, and others are summarized. This review will provide value for the exploration and potential application of membrane chromatography.

Dual receptor NIR-II organic nanoparticles for multimodal imaging guided tumor photothermal therapy.

The second near-infrared (NIR-II) fluorescence imaging has attracted continuous attention due to its excellent penetration depth and high spatial resolution. Compared with other fluorophores, NIR-II fluorophores, especially NIR-II organic small molecule fluorophores, are favored because of their controllable structure and good biocompatibility. In this study, we designed and synthesized an S-D-A-D-S type small molecule FEA. However, a new molecule was accidentally obtained in the process of synthesis, which was proved to be a double receptor (A-A) type small molecule, namely S-D-A-A-D-S type organic small molecule FEAA. Compared with FEA molecules, FEAA exhibits superior fluorescence performance and can effectively prevent fluorescence quenching. The fluorescence emission of its nanoparticles (NPs) reaches 1109 nm, extends to about 1400 nm, and has a Stokes shift of up to 472 nm. Subsequently, we realized fluorescence/photoacoustic dual-mode imaging (FI/PAI) of nude mouse liver, and finally effectively ablated 4T1 tumor by photothermal therapy (PTT). In general, FEAA NPs exhibit good fluorescence, photoacoustic, and photothermal effects, and are an excellent multifunctional NIR-II organic small molecule fluorophore. As far as we know, there are few reports on A-A type organic small molecules, most of which are cyanines or D-A-D type structures. Therefore, this study has good exploratory significance and reference value for the discovery of NIR-II fluorophores.

Natural Polyphenols-Platinum Nanocomplexes Stimulate Immune System for Combination Cancer Therapy.

Nanocarriers have been employed extensively to enhance drug delivery efficacy and reduce the side effect. However, carrier materials for drug delivery have challenging aspects, including safety concerns, low drug content, complexity in preparation, and low reproducibility. Herein, we propose a facile, universal, and green preparation way to use natural polyphenols to build platinum nanocomplex with stable structure, proper size, and high Pt content. The nanocomplexes are constructed by metal-polyphenol coordination using natural polyphenols and 1,2-diaminocyclohexane-Pt (II), enabling dual-responsive drug release behavior. For proof of concept, we demonstrate the antitumor activity of the Pt nanocomplex using a representative tannic acid-Pt nanocomplex (denoted as PTI). PTI can induce intensive tumor cell apoptosis, trigger immunogenic cell death (ICD), remarkably promote cytotoxic T lymphocytes (CTLs) infiltration in tumors, and significantly reduce immunosuppression of the tumor microenvironments, thus stimulating potent antitumor immune responses and showing effective antitumor activity by synergizing immune checkpoint blockade (ICB) therapy.

Regulatory Effects of Three-Dimensional Cultured Lipopolysaccharide-Pretreated Periodontal Ligament Stem Cell-Derived Secretome on Macrophages.

Phenotypic transformation of macrophages plays important immune response roles in the occurrence, development and regression of periodontitis. Under inflammation or other environmental stimulation, mesenchymal stem cells (MSCs) exert immunomodulatory effects through their secretome. It has been found that secretome derived from lipopolysaccharide (LPS)-pretreated or three-dimensional (3D)-cultured MSCs significantly reduced inflammatory responses in inflammatory diseases, including periodontitis, by inducing M2 macrophage polarization. In this study, periodontal ligament stem cells (PDLSCs) pretreated with LPS were 3D cultured in hydrogel (termed SupraGel) for a certain period of time and the secretome was collected to explore its regulatory effects on macrophages. Expression changes of immune cytokines in the secretome were also examined to speculate on the regulatory mechanisms in macrophages. The results indicated that PDLSCs showed good viability in SupraGel and could be separated from the gel by adding PBS and centrifuging. The secretome derived from LPS-pretreated and/or 3D-cultured PDLSCs all inhibited the polarization of M1 macrophages, while the secretome derived from LPS-pretreated PDLSCs (regardless of 3D culture) had the ability to promote the polarization of M1 to M2 macrophages and the migration of macrophages. Cytokines involved in the production, migration and polarization of macrophages, as well as multiple growth factors, increased in the PDLSC-derived secretome after LPS pretreatment and/or 3D culture, which suggested that the secretome had the potential to regulate macrophages and promote tissue regeneration, and that it could be used in the treatment of inflammation-related diseases such as periodontitis in the future.

Aminopeptidase N-Responsive Conjugates with Tunable Charge-Reversal Properties for Highly Efficient Tumor Accumulation and Penetration.

Tumor enzyme-responsive charge-reversal carriers can induce efficient transcytosis and lead to efficient tumor infiltration and potent anticancer efficacy. However, the correlations of molecular structure with charge-reversal property, tumor penetration, and drug delivery efficiency are unknown. Herein, aminopeptidase N (APN)-responsive conjugates were synthesized to investigate these correlations. We found that the monomeric unit structure and the polymer chain structure determined the enzymatic hydrolysis and charge-reversal rates, and accordingly, the transcytosis and tumor accumulation and penetration of the APN-responsive conjugates. The conjugate with moderate APN responsiveness balanced the in vitro transcytosis and in vivo overall drug delivery process and achieved the best tumor delivery efficiency, giving potent antitumor efficacy. This work provides new insight into the design of tumor enzyme-responsive charge-reversal nanomedicines for efficient cancer drug delivery.

Hydrophobicity Effects of γ-Glutamyl Transpeptidase-Responsive Polymers on the Catalytic Activity and Transcytosis Efficacy.

Active transcytosis has recently sparked great interest in drug delivery as a novel route for tumor extravasation and infiltration. However, the rational design of transcytosis-inducing nanomedicines remains challenging. We recently demonstrated that the γ-glutamyl transpeptidase (GGT)-responsive polymer cationization induced efficient adsorption-mediated transcytosis (AMT). However, it remains unclear how the nanomedicines' physicochemical properties influence the GGT-responsive cationization and induced transcytosis behaviors. Herein, through a combination of experimental techniques and molecular dynamics (MD) simulations, we find that the random copolymers with high hydrophobic monomers tend to form compact structures accessible to the catalytic site of GGT, leading to a fast cationization and thus high transcytosis efficiency, while the homopolymers of the hydrophilic GGT-sensitive monomers have elongated structures unable to enter the active site and thus exhibit poor GGT sensitivity. As a result, the more hydrophobic polymer-drug conjugates with high camptothecin contents exhibit higher GGT-responsive activity, which in turn leads to faster cationization and cellular internalization, enhanced tumor infiltration, and more potent antitumor activity. These findings indicate the hydrophobicity is a main parameter determining the GGT catalytic activity and transcytosis efficiency of the GGT-activatable co(homo)polymers, providing guidelines for the rational design of GGT-induced charge reversal carriers for transcytotic nanomedicines.

Glutathione-Responsive Magnetic Nanoparticles for Highly Sensitive Diagnosis of Liver Metastases.

Liver metastasis (LM) occurs in various cancers, and its early and accurate diagnosis is of great importance. However, the detection of small LMs is still a great challenge because of the subtle differences between normal liver tissue and small metastases. Herein, we prepare glutathione (GSH)-responsive hyaluronic acid-coated iron oxide nanoparticles (HIONPs) for highly sensitive diagnosis of LMs through a facile one-pot method. HIONPs greatly enhance the signal of MRI in tumor metastases as T1 contrast agent (CA), whereas they substantially decrease the signal of liver as T2 CA as they aggregate into clusters upon the high GSH in liver. Consequently, MRI contrasted by HIONPs clearly distinguishes metastatic tumors (bright) from surrounding liver tissues (dark). HIONPs with superior LM contrasting capability and facile synthesis are very promising for clinical translation and indicate a new strategy to develop an ultrasensitive MRI CA for LM diagnosis that exploits high GSH level in the liver.

Molecularly Precise, Bright, Photostable, and Biocompatible Cyanine Nanodots as Alternatives to Quantum Dots for Biomedical Applications.

Fluorescent imaging with fluorophores has become a powerful way to explore complex biological systems and visualize nanoparticles for drug delivery. However, it is challenging to develop fluorophores with ideal physical and optical properties. We report a method to synthesize cyanine nanodots with a single-molecule structure, well-defined particle size, customizable fluorescent spectrum, and bright and stable fluorescence. These cyanine nanodots are acquired by the divergent synthesis of cyanine-dye-cored polylysine (PLL) dendrimers. We demonstrated the feasibility of the method by synthesizing cyanine 3 (Cy3), cyanine 5 (Cy5), or cyanine 7 (Cy7) cored single-molecule nanodots up to eight generations with a size of around 11 nm. We show that these cyanine nanodots are capable of multiple biomedical applications, including multicolor cellular tracing and cancer imaging. These cyanine nanodots possess many merits of organic dots and quantum dots that are promising for future application.

An Orthogonal Dynamic Covalent Polymer Network with Distinctive Topology Transformations for Shape- and Molecular Architecture Reconfiguration.

Bond exchange in a typical dynamic covalent polymer network allows access to macroscopic shape reconfigurability, but the network architecture is not altered. An alternative possibility is that the network architecture can be designed to switch to various topological states corresponding to different material properties. Achieving both in one network can expand the material scope, but their intrinsically conflicting mechanisms make it challenging. We design a dynamic covalent network that can undergo two orthogonal topological transformations, namely transesterification on the branched chains and olefin metathesis on the mainframe. This allows independent control of the macroscopic shape and molecular architecture. With this design, we illustrate a bottlebrush network with programmable shape and spatially definable mechanical properties. Our strategy paves a way to on-demand regulation of network polymers.

Effect of Cationic Charge Density on Transcytosis of Polyethylenimine.

The adsorption-mediated transcytosis (AMT) induced by the electrostatic interaction between the positively charged surface of carriers and negatively charged cell membrane is a new paradigm enabling nanomedicine's tumor extravasation and infiltration. However, little is known about the correlation between the carrier's charge density and its AMT-induced tumor infiltration efficiency. Herein, we investigate the effect of the cationic polymer's charge on the AMT-induced tumor penetration ability using in vitro multilayer tumor spheroids (MTSs). A cationic polymer, polyethylenimine (PEI), is amidized with acetic anhydride to obtain acetylated PEIs (AcPEIs) with different cationic charge densities. As the amidization ratio increases, the AcPEIs' cytotoxicity, zeta potential, and cell-binding affinity significantly decrease. Notably, not only does the weak cell binding (AcPEIs with high acetylation degrees) lead to slow endocytosis and inefficient transcytosis, so does the strong cell-binding PEI. The PEI with 24% acetylation (AcPEI24%) is found to have the highest transcytosis efficiency because its balanced cell-binding affinity triggers fast adsorption-mediated endocytosis. The subsequent Golgi apparatus/endoplasmic reticulum-mediated exocytosis via extracellular vesicles leads to highly effective transcellular delivery and tumor penetration in MTSs. Therefore, the drug carrier's surface cationic charge density critically influences its AMT-induced tumor penetration efficiency. This study provides mechanistic insights into the design of drug-delivery systems with active transcytosis for improved tumor penetration and enhanced therapeutic efficiency.

Analysis of proteins and chiral drugs based on vancomycin covalent capillary electrophoretic coating.

Vancomycin is an amphoteric glycopeptide molecule, and its group diversity and chiral active sites provide a potential basis for its application in chromatographic analysis. In this article, using photosensitive diazo resin (DR) as the coupling agent, vancomycin is modified on the inner wall of the capillary to construct a capillary coating separation system. The highlight of the coated capillary is that it has both anti-protein adsorption and chiral separation properties. Compared with the bare capillary or non-covalently bonded DR/vancomycin-coated capillary, it can not only achieve the separation of four mixed proteins of lysozyme (Lys), bovine serum albumin (BSA), myoglobin (Mb), and ribonuclease A (RNase A), but also shows excellent performance in chiral drugs. The coated capillary effectively solves the problems of low efficiency of the separation column and high sample loss and provides ideas for the development of coated capillaries in the future.