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Graphical Abstract Infectious diseases, such as the coronavirus disease-19, SARS virus, Ebola virus, and AIDS, threaten the health of human beings globally. New viruses, drug-resistant bacteria, and fungi continue to challenge the human efficacious drug bank. Researchers have developed a variety of new antiviral and antibacterial drugs in response to the infectious disease crisis. Meanwhile, the development of functional materials has also improved therapeutic outcomes. As a natural material, chitosan possesses good biocompatibility, bioactivity, and biosafety. It has been proven that the cooperation between chitosan and traditional medicine greatly improves the ability of anti-infection. This review summarized the application and design considerations of chitosan-composed systems for the treatment of infectious diseases, looking forward to providing the idea of infectious disease therapy.

Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) gene editing technology is a promising approach for cancer therapy, and its application practice urgently requires a safe and effective gene carrier. In this work, we focus on the design of a phenylboronic acid (PBA)-functionalized, disulfide bonded branched polyaminoglycoside (SS-HPT-P) as a robust delivery vector of the CRISPR-Cas9 system. SS-HPT-P showed great tumor-targeting performance, reduction-responsive degradability, and gene transfection ability. The typical pCas9-surv (one CRISPR-Cas9 plasmid that targets and knocks out the survivin gene) delivery mediated by SS-HPT-P exhibited gene editing performance in the A549 cell line, confirming the feasibility of SS-HPT-P to effectively deliver the CRISPR-Cas9 system. SS-HPT-P/pCas9-surv could effectively inhibit the proliferation of tumor cells both in vitro and in vivo, suggesting the potential of PBA-functionalized nanocarriers for cancer gene therapy. The present work provides a promising approach for the treatment of malignant tumors.

Inflammation has been assumed to affect the pathology of wound healing and is associated with many nonhealing chronic wounds. Naturally derived herbal medicines with anti-inflammatory properties are of interest because of their effectiveness and affordability in clinical treatment. Herein, we report a supramolecular hydrogel comprising self-assembled natural herb rhein and an oxidative responsive cross-linked network based on ferrocene and β-cyclodextrin host-guest recognitions. Rhein can directly self-assemble into fibrils, exerting better anti-inflammation efficiency than its free drug form. The adaption of the supramolecular network can greatly improve the stability and retain the structural integrity of encapsulated self-assembled rhein. In addition, host-guest recognition confers dissolution of the hydrogel under oxidative stress, thereby delivering self-assembled rhein to the wound site and exerting better therapeutic efficiency. Evaluations in diabetic mice indicate that the resultant hydrogel promoted chronic wound healing by suppressing excess reactive oxygen species, facilitating the transition of the wound healing process, and restoring the normal wound-repair process. Therefore, the proposed hydrogel has a potential value as an herbal-based dressing for future clinical chronic wound management.

Supramolecular hydrogels confer control over structural properties in a reversible, dynamic, and biomimetic fashion. The design of supramolecular hydrogels with an improved structural and functional recapitulation of damaged organs is important for clinical applications. For wound healing management, in particular, an effective healing process, through the modulation of epidermal growth factor (EGF) delivery using supramolecular polysaccharide hydrogels, has yet to be developed. In this study, photo-responsive supramolecular polysaccharide hydrogels were formed through host-guest interactions between azobenzene and β-cyclodextrin groups conjugated to hyaluronic acid chains. By exploiting the photoisomerization properties of azobenzene under different wavelengths, a supramolecular hydrogel featuring a dynamic spatial network crosslink density through the application of a light stimulus was obtained. Under ultra violet (UV) light, the loosened hydrogel can rapidly release EGF, thereby enhancing EGF delivery at the wound site. Based on an in vivo assessment of the healing process through a full-thickness skin defect model, the controlled EGF release from a supramolecular hydrogel exhibited superior wound healing efficiency with respect to granulation tissue formation, growth factor levels, and angiogenesis. Therefore, the proposed supramolecular hydrogels are potentially valuable as controlled delivery systems for future clinical wound healing applications.

Fused deposition modelling (FDM) is a commonly used 3D printing technology. The development of FDM materials was essential for the product quality of FDM. In this work, a series of polycaprolactone (PCL)-based composites for low-temperature FDM were developed. By melt blending technique, different ratios of starch were added into PCL to improve the performances of FDM, and the printability, tensile strength, rheological properties, crystallization behaviors and biological performances of the composites were studied. The PCL/starch composite had the best performance in FDM process with the starch ratio of 9 ph at 80–90 °C. The melting strength and solidification rate of PCL/starch composites were improved. The starch also increased the crystallization temperature, degree of crystallinity and crystallization rate of PCL/starch composites, while had no negative effects on the tensile strength of PCL. Due to the low printing temperature, various kinds of bioactive components were added into PCL/starch composites for preparation of antibacterial and biocompatible materials for FDM. The present work provides a new method to develop novel low-temperature FDM materials with various functions., Graphical abstract Image 1, Highlights • PCL/starch composites for low-temperature fused deposition modelling were developed. • The tensile strength, rheological properties and crystallization behaviors of PCL/starch composites were studied. • Bioactive components were added to functionalize the composites with antibacterial and biocompatible properties.

Cancer immunotherapy provides an effective way to deal with cancer. Although immunotherapy strategies have shown encouraging therapeutic effects, the inherent limitations of immunotherapy, such as multiple tumor immune evasion methods, low response rate, and systemic toxicity, still hinder its clinical applications. In recent decades, nanomaterials have been considered promising in cancer immunotherapy since they can realize targeted delivery and interact with the immune system to induce or enhance the antitumor immune responses. Among them, organic/inorganic nanocomposites are ideal candidates for cancer immunotherapy since they could combine the advantages of both organic and inorganic components. Multifunctional organic/inorganic nanocomposites could help overcome the shortcomings of current cancer immunotherapy, and realize the combination of immunotherapy and other therapeutic strategies with synergistic antitumor effects. Herein, we review the recent progress of organic/inorganic nanocomposites designed for cancer immunotherapy. The immunotherapy strategies of nanocomposites are summarized from the perspective of achieving immune enhancement. The challenges of nanocomposites in cancer immunotherapy are also discussed.

Tunable adhesion of different cell types on well-defined surfaces has attracted common interests in the field of biomaterial science and surface engineering. Herein, we demonstrate a new strategy for the regulation of cell adhesion by simply controlling the thickness of thermoresponsive poly(N-isopropylacrylamide) (PNIPAAm) brushes via surface-initiated atom transfer radical polymerization (ATRP). The adhesion of different cell types (4T1, HEK293, H9C2, HUVEC, and L929) can be easily modulated by varying the thickness of PNIPAAm brushes from 5.9 ± 1.0 nm (PN1) to 69.0 ± 5.0 nm (PN6). The fluorescent staining of different cell types on a variety of surfaces reveals that the thickness of PNIPAAm brushes would regulate the assembly of F-actin and the expression of vinculin and fibronectin, which are essential in regulating the adherent status of cells. Moreover, the cellular morphologies revealed that the adherent cells are well-spread, and multiple pseudopod extensions and protrusions can be observed at the margin of cells. This work provides a facile strategy for regulating tunable adhesion of different cell types, which may find applications in tissue engineering and regenerative medicine.

Catheter-related infection is a great challenge to modern medicine, which causes significant economic burden and increases patient morbidity. Hence, there is a great requirement for functionalized surfaces with inherently antibacterial properties and biocompatibility that prevent bacterial colonization and attachment of blood cells. Herein, we developed a strategy for constructing polymer brushes with hierarchical architecture on polyurethane (PU) via surface-initiated atom-transfer radical polymerization (SI-ATRP). Surface-functionalized PU (PU-DMH) was readily prepared, which comprised of poly(3-[dimethyl-[2-(2-methylprop-2-enoyloxy)ethyl]azaniumyl]propane-1-sulfonate) (PDMAPS) brushes as the lower layer and antimicrobial peptide-conjugated poly(methacrylic acid) (PMAA) brushes as the upper layer. The PU-DMH surface showed excellent bactericidal property against both Gram-positive and Gram-negative bacteria and could prevent accumulation of bacterial debris on surfaces. Simultaneously, the PU-DMH samples possessed good hemocompatibility and low cytotoxicity. Furthermore, the integrated antifouling and bactericidal properties of PU-DMH under hydrodynamic conditions were confirmed by an in vitro circulating model. The functionalized surface possessed persistent antifouling and bactericidal performances both under static and hydrodynamic conditions. The microbiological and histological results of animal experiments also verified the in vivo anti-infection performance. The present work might find promising clinical applications for preventing catheter-related infection.

Multifunctional antibacterial materials have great significance for treating biomedical device-associated infections (BAIs). In the present work, a facile and rational strategy was developed to produce dual-functional implants with antibacterial and osteointegration-promoting properties for the treatment of BAI. A titanium implant, as a representative demo of implants, was first functionalized with ethanediamine-functionalized poly(glycidyl methacrylate) (PGED) brushes. Then, low-molecular-weight quaternized polyethyleneimine (QPEI, a cationic antibacterial agent) and alendronate (ALN, a clinically used drug with high affinity for bone minerals) were covalently conjugated onto PGED brushes to produce dual-functional dental implants (Ti-AQ). The QPEI component imparted Ti-AQ with antibacterial abilities, and the ALN component could balance the cytotoxicity of a cationic antibacterial agent, improving the biocompatibility for osteoblast cells. The effective performances of anti-infection and osteointegration were demonstrated in a BAI animal model. The results indicated that Ti-AQ inhibited bacterial infection at the early stage and enhanced the osteointegration and biomechanical properties between the implants and bone tissues at the late stage. This study will provide one facile and universal strategy for the design and development of novel multifunctional antibacterial implants.

由多糖和多功能无机纳米颗粒组成的多糖基复合纳米材料在生物医学领域具有潜在的应用价值, 是一种有希望的候选材料. 本文介绍了多糖基复合纳米材料的优良性能及其在成像和治疗中的应用. 除了多糖和无机纳米颗粒这两部分的功能简单结合以外, 复合纳米材料还具有协同性能和功能. 最后, 我们讨论了多糖基复合纳米材料在潜在的临床应用中的挑战和前景.

Infections caused by multidrug resistant bacteria are still a serious threat to human health. It is of great significance to explore effective alternative antibacterial strategies. Herein, carbon-iron oxide nanohybrids with rough surfaces (RCF) are developed for NIR-II light-responsive synergistic antibacterial therapy. RCF with excellent photothermal property and peroxidase-like activity could realize synergistic photothermal therapy (PTT)/chemodynamic therapy (CDT) in the NIR-II biowindow with improved penetration depth and low power density. More importantly, RCF with rough surfaces shows increased bacterial adhesion, thereby benefiting both CDT and PTT through effective interaction between RCF and bacteria. In vitro antibacterial experiments demonstrate a broad-spectrum synergistic antibacterial effect of RCF against Gram-negative Escherichia coli (E. coli), Gram-positive Staphylococcus aureus (S. aureus), and methicillin-resistant Staphylococcus aureus (MRSA). In addition, satisfactory biocompatibility makes RCF a promising antibacterial agent. Notably, the synergistic antibacterial performances in vivo could be achieved employing the rat wound model with MRSA infection. The current study proposes a facile strategy to construct antibacterial agents for practical antibacterial applications by the rational design of both composition and morphology. RCF with low power density NIR-II light responsive synergistic activity holds great potential in the effective treatment of drug-resistant bacterial infections.

Hydrogels with improved mechanical properties can expand to a greater range of applications. The fabrication of conventional toughened hydrogels typically requires precise modifications, multiple components, and complex steps. Here, a straightforward "one-step" polymerization method for the in situ preparation of hydrogels in aqueous solutions, is reported. Inspired by polymerization-induced self-assembly (PISA), water-miscible monomers are copolymerized during the hydrogel fabrication; the growing blocks eventually form physical bridges thus providing a mechanism for effective energy dissipation. The rheological and mechanical properties are evaluated and the results reveal that this strategy can be an effective approach to design mechanically enhanced hydrogels for a wide range of applications.

It is of great significance to develop multifunctional gene carriers to achieve treatments with enhanced therapeutic effects in an inflammation-free manner. In this work, assembled micelles of polysaccharide were utilized for the biomineralization of calcium carbonate to produce one-dimensional Alg-CaCO3 nanoparticles. In order to introduce both functions of mild hyperthermia and gene transfection, polydopamine (PDA) coating was applied to conjugate cationic polymers on the surface of nanoparticles. The resultant ACDP nanohybrids exhibited enhanced performance as gene carriers under near infrared (NIR) light irradiation at a low power density. Meanwhile, the pH-responsive degradation of gene carriers could further promote gene release for better effectiveness. The enhanced gene therapy induces tumor cell apoptosis, which could prevent inflammatory responses. The feasibility of mild hyperthermia-enhanced gene therapy for tumor treatment was investigated in vitro and in vivo. In addition, dual-modal ultrasound (US) and photoacoustic (PA) imaging was also realized to monitor and guide the treatment processes. The current work provides a new avenue for the construction of multifunctional platform to realize cancer therapy with improved therapeutic effectiveness in an inflammation-free manner.

There is an increasing demand for developing new materials and approaches for rapid and sensitive detection of protease biomarkers. Herein, the poly(methacrylic acid) (PMAA) brushes were synthesized from silica nanoparticles via surface-initiated atom transfer radical polymerization (ATRP), and flexibly functionalized with different fluorescein-labeled peptides, serving as the substrates for protease assay. To facilitate the point-of-care detection of protease, polyacrylamide gel pad arrays were fabricated to allow permeation of fluorescein-labeled peptide fragments cleaved from the PMAA brushes. This experimental setup enables an on-chip protease assay with an adequate limit of detection (LOD) for detecting trypsin in a buffer solution (3.9 pM) or in serum (1.4 nM) and good specificity for differentiation of trypsin and chymotrypsin. By using this experimental setup, matrix metalloproteinase-2 and matrix metalloproteinase-9 can be detected with LODs of 2.5 nM and 3.3 nM, respectively. Moreover, by introducing an adamantine (Ad) motif to the side-chain of the peptide fragment and β-cyclodextrin (β-CD) groups to the gel pad matrix, a 2.2-fold lower LOD was achieved for the detection of trypsin (1.8 pM) due to the supramolecular self-assembly of Ad and β-CD. Given the advances in the ease of sample handling, this rational design of peptide-functionalized PMAA brushes could be useful for on-chip detection of protease biomarkers or the screening of potential protease inhibitors.

It is very desirable to develop advanced sustainable biomedical materials with superior biosafety and bioactivity for clinical applications. Herein, biomass‐derived multilayer‐structured absorbable microparticles (MQxTy) composed of starches and plant polyphenols are readily constructed for the safe and effective treatment of bone defects with intractable bleeding by coating multiple layers of quaternized starch (Q+) and tannic acid onto microporous starch microparticles via facile layer‐by‐layer assembly. MQxTy microparticles exhibit efficient degradability, low cytotoxicity, and good blood compatibility. Among various MQxTy microparticles with distinct Q+/T− double layers, MQ2T2 with outmost polyphenol layer possess the unique properties of platelet adhesion/activation and red blood cell aggregation, resulting in the best hemostatic performance. In a mouse cancellous‐bone‐defect model, MQ2T2 exhibits the favorable hemostatic effect, low inflammation/immune responses, high biodegradability, and promoted bone repair. A proof‐of‐concept study of beagles further confirms the good performance of MQ2T2 in controlling intractable bleeding of bone defects. The present work demonstrates that such biomass‐based multilayer‐structured microparticles are very promising biomedical materials for clinical use., Biomass‐derived multilayer‐structured hemostatic microparticles (MQ2T2) composed of starches and plant polyphenols are constructed to integrate the advantages of cationized amylopectin (with high viscosity), polyphenol (with unique properties in accelerating hemostasis), and multilayer structures (with favorable biodegradability), which can achieve effective (accelerated hemostasis and promoted bone repair) treatments of bone defects with intractable bleeding in mouse and beagle models.

Gene editing is a crucial and effective strategy to treat genetic diseases. Safe and effective delivery vectors are specially required for efficient gene editing in vivo of CRISPR/Cas9 system. Interestingly, lactose, a natural saccharide, can specifically bind to asialoglycoprotein receptors, highly expressed on the surface of hepatocellular carcinoma (HCC) cells. Herein, a lactose‐derived branched cationic biopolymer (LBP) with plentiful reducible disulfide linkages and hydroxyl groups is proposed as a potential delivery vector of CRISPR/Cas9 system for efficient genome editing in vivo to treat orthotopic HCC. LBP is synthesized via a facile one‐pot ring‐opening reaction. LBP possesses excellent compacting ability, degradability, biocompatibility, gene transfection performances, and HCC‐targeting ability. LBP‐mediated delivery of classical pCas9‐survivin, which can target and knockout survivin oncogene, produces efficient gene editing performances, and superb anti‐cancer activities in orthotopic HCC mouse models. This study provides an attractive and safe strategy for the rational design of CRISPR/Cas9 delivery system., A polyhydroxy, reduction‐responsive degradable lactose‐derived branched cationic biopolymer is proposed as a safe and effective CRISPR/Cas9 delivery system for targeted therapy in orthotopic hepatocellular carcinoma.

Magnetic assemblies with special morphologies are promising for versatile biomedical applications due to their intriguing properties and performances. In this work, a polycation-functionalized bowl-shaped magnetic assembly (b-MNP-PGEA) was constructed for magnetic resonance imaging (MRI)-guided synergistic cancer therapy. Taking advantage of distinct properties of Fe3O4 nanoparticles, self-assembly concept, morphology control, and appropriate surface functionalization, the as-prepared magnetic assembly with special morphology was expected to work as a multifunctional carrier to realize the combination of magnetofection and photothermal therapy (PTT). The morphology effect of the magnetic assembly on cellular uptake and the subsequent gene transfection were investigated. The feasibility of the magnetic and photothermal carriers for MRI and complementary PTT/gene therapy was also studied. In addition, the excellent in vivo performance of the proposed bowl-shaped multifunctional carriers was demonstrated using a mouse breast cancer model. Interestingly, synergistic effects based on PTT-enhanced gene therapy were achieved. The facile assembly strategy for the development of special bowl-shaped magnetic carriers for synergistic PTT/gene therapy provides a new avenue for the versatile construction of efficient theranostic platforms.

Fluorescence-based theranostics provides a powerful platform for effective diagnosis and therapy. In particular, luminogens with aggregation-induced emission (AIE) characteristics have triggered state-of-the-art developments in theranostics, thanks to their intrinsic properties, including high signal-to-noise ratios, high photostability and capability as photosensitizing agents. However, the development of AIE luminogens for biological applications mostly stays at rational design and preparation through organic synthesis, which may give rise to high cost, environmental destruction and potential cytotoxicity. Actually, with easy access and good biocompatibility, it would be of great interest to employ AIE-active natural agents from herbs in theranostics and pharmacodynamics studies through fluorescence imaging. In this work, the use of berberine chloride, an AIE-active natural product from herbal plants, as a theranostic agent towards both cancer cells and bacteria is investigated. Through fluorescence bio-imaging, berberine chloride selectively targets cancer cells over normal cells and discriminates Gram-positive against Gram-negative bacteria. Furthermore, light-driven organelle-targeting migration of berberine chloride from mitochondria to the nucleus was discovered. Therapeutic evaluation shows that berberine chloride can efficiently ablate cancer cells over normal cells, and kill Gram-positive bacteria through both in vitro and in vivo photodynamic therapy. This work thus provides a blueprint for the next generation of theranostics using natural AIE luminogens.

The design of novel antibacterial materials has attracted increasing attention for combating bacterial infections. Herein, we conjugated zinc(ii) monoamino phthalocyanine (ZnMAPc) to poly(glycidyl methacrylate) (PGMA) via a ring-opening reaction, and the excess epoxy groups were scavenged by ethylenediamine (ED). The resultant macro-photosensitizer (PGED-Pc) can be easily dispersed in aqueous solution to form self-assembled nanoparticles and generate reactive oxygen species for inactivation of bacteria when exposed to light illumination. We found that the photodynamic pathway for the generation of singlet oxygen (1O2) was strongly inhibited in aqueous solution, and the major components for the inactivation of bacteria were superoxide anion radicals (˙O2-) and hydrogen peroxide (H2O2), which could result in the disruption of bacterial envelopes, the inactivation of vital enzymes, and the degradation of genomic DNA. PGED-Pc exhibited potent photodynamic antibacterial activity, with minimum bactericidal concentration (MBC, defined as 99.9% inactivation of bacteria) values of 128 μg mL-1 for Escherichia coli (E. coli) and 4 μg mL-1 for Staphylococcus aureus (S. aureus). As a proof-of-concept, the PGED-Pc nano-assemblies in aqueous solution can be readily immobilized on glass slides via a Schiff-base reaction, and impose potent photodynamic antibacterial activity upon light illumination. This work unveils a promising strategy for the engineering of self-sterilizing surfaces to combat bacterial infections.

This work reports a study of electropolymerization kinetics, film thickness, stability, and antifouling properties of polydopamine (PDA) and its three analogues: poly(3-(3,4-dihydroxyphenyl)-l-alanine) (PL-DOPA), poly(5-hydroxytryptophan) (PL-5-HTP), and poly(Adrenalin) (PAdrenalin). It was observed that the number of the hydroxyl groups on the benzene ring and the type (primary vs secondary) of amine group significantly affect the electropolymerization kinetics and thus the thickness of the obtained polymer films. Monomers with two hydroxyl groups (except Adrenalin) resulted in films that were thicker (∼10-15 nm) than the one with only one hydroxyl group (PL-5-HTP) (∼5-8 nm) under similar conditions. Adrenalin containing a secondary amino group could not be deposited onto the ITO substrate, while the other three compounds containing a primary amino group completely covered the ITO. The PDA films had better electrochemical stability than the other films. No film showed stable antifouling surfaces against protein.

Multifunctional organic/inorganic nanocomposites are highly attractive for effective biomedical applications. In this work, versatile types of self-destructible polysaccharide (dextran or pullulan) nanocomposites (denoted Au@PSa) with adjustable amounts of unlockable Au nanorods (Au NRs) were fabricated as highly efficient photothermal cancer therapy systems. Taking advantage of the acidic endosomes and high concentration of glutathione (GSH) present in cancer cells, the responsive self-destruction of Au@PSa nanocomposites could unlock the abundant encapsulated Au NRs within cells. Notably, the pullulan-based nanocomposites (denoted Au@Pul) demonstrated liver cell-targeting properties, which could enhance the therapeutic effects while minimizing side effects. The strong absorption of the unlocked Au NRs in the near-infrared region was utilized to examine the photothermal performance. The Au@PSa nanocomposites with a moderate amount of Au NRs in the matrix exhibited very impressive photothermal effects in tumor therapy, where the encapsulated Au NRs were unlocked in the tumor region to realize the observed high performance. The proposed system could be further extended, as the polysaccharides were functionalized with amino groups. The current work provides a facile strategy to construct flexible therapeutic platforms with responsive self-destruction features. A strategy that relies on polysaccharides and gold nanorods to realize cancer therapy shows promise in live animal studies. In photothermal therapy, nanoparticles in cancerous tissue convert laser light into heat and damage tumors while leaving surrounding healthy tissue unharmed. Nana Zhao and Fu-Jian Xu from the Beijing University of Chemical Technology in China and colleagues synthesized polysaccharide-based nanocapsules that can encapsulate photothermal gold nanorods (pullulan-gold nanocomposites), and simultaneously target asialoglycoprotein receptor overexpressed liver cancer cells. Using real-time confocal laser scanning microscopy, the team demonstrated that the nanocomposites rapidly accumulated around the nuclei of hepatoma cells, where acidic conditions dissolved the polysaccharide matrix and unleashed gold nanorods with the assistance of glutathione. Images taken after photothermal therapy in mice revealed massive shrinking of cancerous cells and fragmented nuclei, with no side effects on major organs. Versatile types of self-destructible polysaccharide nanocomposites with adjustable amounts of unlockable Au nanorods were fabricated for highly efficient photothermal cancer therapy systems.

Safe and effective vectors play an important role in nucleic acid delivery processes. Ring-opening reactions are quite often used to produce biomaterials with various functions and properties. Instead of surface-conjugated hydrophilic polymers such as polyethylene glycol, uniformly-distributed hydroxyl groups within one polycation could improve biocompatibility and benefit nucleic acid delivery performances. Hydroxyl groups with uniform distribution are readily produced by ring-opening of O -heterocyclic units. O -Heterocyclic units include cyclic ester (epoxide), carbonate and lactones . Hydroxyl-rich polycationic systems are prepared predominately with aminated poly(glycidyl methacrylate) (PGMA). PGMA is the most common epoxy polymer and can be post-modified readily via epoxide ring-opening reactions by different amine species. Hydroxyl-rich polycationic systems are also reported by ring-opening polymerization between various epoxy and amine units. In addition, post hydroxylation of polycations via different O -heterocyclic ring-opening reactions could give rise to various hydroxyl-rich polycationic systems. More recently, versatile types of hydroxyl-rich polycationic systems with special molecular and topological structures, such as linear, star-shaped, comb-shaped, supramolecular, branched, hierarchical, and hetero-nanostructured carriers, are well studied. This review summarizes recent research activities in hydroxyl-rich polycationic systems. Their different design strategies via O -heterocyclic ring-opening reactions and unique nucleic acid delivery applications are described in detail. The research activities indicate that hydroxyl-rich polycationic systems become versatile and powerful candidates for the development of advanced multifunctional delivery systems of nucleic acids.

Effective hemostatic materials are very important for treating trauma cases. Natural polysaccharides have been particularly appealing in the development of new hemostatic materials due to their unique functions in human bodies. In this work, different polysaccharide-based hemostatic porous sponges (SHDP or SHDQ) of cross-linked hyaluronic acid (HA)/cationized dextran were readily prepared by the self-foaming process of HA and poly((2-dimethyl amino)-ethyl methacrylate)-grafted dextran (Dex-PDM) or partially-quaternized Dex-PDM in the presence of sodium trimetaphosphate crosslinkers. SHDP and SHDQ sponges were investigated in terms of liquid-absorption ability, hemolysis, whole-blood clotting and hemostatic activity in hemorrhaging-liver models. Compared with HA/Dex-PDM sponges (HDP) without chemical cross-linking, SHDP and SHDQ sponges displayed higher porosity (>70.0% vs. 48.9%) and swelling ratios (>1000% vs. 520%). Meanwhile, hemolysis assay revealed the good blood compatibility of SHDP and SHDQ with low hemolysis ratio (below 0.5%). Furthermore, in vitro and in vivo hemostatic assay showed that SHDQ possessed better hemostatic properties than SHDP, owing to the higher cationic charges of partially-quaternized Dex-QPDM than Dex-PDM. The present study demonstrated that the self-foaming process of HA/Dex-PDM under a 'green' condition is an effective means to produce new hemostatic materials.

Bone defects represent a clinical challenge that severely impacts the quality of life of affected patients. To match the shape of a bone defect area exactly, additive manufacturing has emerged as a promising technology to produce customized bone regeneration scaffolds for bone defect treatment. In this study, new three-dimensional (3D)-printed poly(L-lactic acid) (PLLA)/hydroxyapatite (HA) composite scaffolds were developed. HA nanoparticles were first modified by a straightforward, economical method. Briefly, HA nanoparticles were modified with dopamine and hexamethylenediamine, and PLLA chains were grafted onto the HA nanoparticles by aminolysis reaction. Then, the PLLA-modified HA nanoparticles were blended with PLLA to form a thermoplastic composite for 3D printing. Due to the high compatibility between the PLLA matrix and PLLA-modified HA nanoparticles, the 3D-printed PLLA/HA scaffolds possess robust mechanical properties and good biocompatibility. This study provides a flexible strategy to fabricate scaffolds for the customized treatment of bone defects.

A zwitterionic poly(sulfobetaine-3,4-ethylenedioxythiophene) (PSBEDOT)-based glucose biosensor was fabricated via encapsulating glucose oxidase (GOx) in a one-step electropolymerization method. Integrating conductivity and hydrophilic properties, PSBEDOT provides a great framework for GOx immobilization and stabilization. The anti-fouling, high-sensitivity, and long-term stability properties of PSBEDOT–GOx make it a promising platform for long-term and continuous glucose monitoring.

Nucleic acid (NA)-based therapy was put forward as a promising method to conquer serious human diseases. Safe and robust gene vectors play an important role in NA delivery processes. In this work, a novel ABA-triblock hydroxyl-rich cationic polyrotaxane PP-PGEA, consisting of one polyethylene glycol backbone, CD-PGEA (composed of one cyclodextrin (CD) core and three ethanolamine (EA)-functionalized poly(glycidyl methacrylate) arms) assembly units, and degradable end-capping polypeptide segments, was prepared as a promising NA delivery system. PP-PGEA has low cytotoxicity and degradability, beneficial to the NA delivery process. The breakdown of end-capping polypeptides could benefit the disassembly of PP-PGEA within cells. PP-PGEA demonstrated substantially higher transfection performances than CD-PGEA assembly units. PP-PGEA was also shown to possess remarkable anti-cancer capability through glioma models. Such a high-performance cationic polyrotaxane with terminal polypeptides would provide a very promising means to produce efficient delivery vectors of versatile NAs.

The development of new hetero-nanostructures for multifunctional applications in cancer therapy has attracted widespread attention. In this work, we put forward a facile approach to synthesize multifunctional hetero-nanostructures of cellulose nanocrystal (CNC)-gold nanoparticle hybrids wrapped with low-toxic hydroxyl-rich polycations to integrate versatile functions for effective cancer therapy. Biocompatible CNCs with the superior rod-like morphology for high cellular uptake were employed as substrates to flexibly load spherical gold nanoparticles (Au NPs) or gold nanorods (Au NRs) through gold-thiolate bonds, producing hetero-layered nanohybrids of CNC-Au NPs or CNC-Au NRs. Profound hydroxyl-rich cationic gene carrier, CD-PGEA (comprising β-cyclodextrin cores and ethanolamine-functionalized poly(glycidyl methacrylate) arms), was then assembled onto the surface of CNC-Au nanohybrids through host-guest interaction and gold-thiolate bonds, where PEG was employed as the intermediate and spacer. The resultant CNC-Au-PGEA hetero-nanostructures exhibited excellent performances as gene carriers. Furthermore, CNC-Au NR-PGEA comprising Au NRs demonstrated favorable optical absorption properties and were validated for photoacoustic imaging and combined photothermal/gene therapy with considerable antitumor effects. The present work provided a flexible strategy for the construction of new multifunctional hetero-nanostructures with high antitumor efficacy.

Nowadays, nucleic acid-based therapy has become a promising way for the treatment of various malignant diseases like cancers. However, the process of nucleic acid delivery is hampered by several extracellular and intracellular obstacles. To overcome these obstacles, many nucleic acid delivery carriers have been developed to achieve improved safety and enhanced gene transfection performance. Among these carriers, degradable branched polycations have attracted much attention due to their good responsive degradability and impressive transfection performances. In this review, we mainly summarized the redox- and pH-responsive degradable branched polycationic systems used for nucleic acid delivery. For responsive degradable branched polycationic systems, the preparation methods were introduced, where amino-epoxy ring-opening reaction as a novel step growth approach was mainly presented. The properties of redox- and pH-responsive degradable branched polycationic systems were subsequently introduced and highlighted. We hope this brief review will motivate the delicate design of responsive degradable branched polycationic systems for potential clinical applications. This article is categorized under: Biology-Inspired Nanomaterials > Nucleic Acid-Based Structures.

Polymer-inorganic hybrid nanomaterials have attracted much attention for the multimodal cancer therapy, while it is still desirable to explore hybrids with superior morphologies for two or more therapeutic modalities. In this work, four types of carbon nanoparticles with distinct morphologies were prepared by an elaborate template-carbonization corrosion process and then functionalized with a similar amount of the superior polycationic gene vector, CD-PGEA [consisting of one β-cyclodextrin core (CD) and two cationic ethanolamine-functionalized poly(glycidyl methacrylate) (PGEA) arms] to evaluate the morphology-influenced gene and photothermal (PT) therapy. Benefiting from the starting rough hollow nanosphere (RHNS) core, the resultant nanohybrids RHNS-PGEA exhibited the highest gene transfection (including luciferase, fluorescent protein plasmid, and antioncogene p53) and NIR PT conversion efficiency among the four types of nanohybrids. Moreover, the efficient PT effect endowed RHNS-PGEA with PA imaging enhancement and an effective imaging guide for the tumor therapy. In addition, anticancer drug 10-hydroxy camptothecin was successfully encapsulated in RHNS with polycation coating, which also displayed the second near-infrared (NIR-II)-responsive drug release. Taking advantages of the superior gene delivery/PT effect and NIR-II-enhanced drug delivery, RHNS-PGEA realized a remarkable therapeutic effect of trimodal gene/PT/chemotherapy of malignant breast cancer treatment in vitro and in vivo. The present work offers a promising approach for the rational design of polymer-inorganic nanohybrids with superior morphology for the multimodal cancer therapy.

Multimodal therapy has been continuously explored for different diseases. Photodynamic/gene combined therapy is a promising treatment strategy of tumor. However, the limitation of traditional chemical photosensitizer and the asynchronism of the two therapies restrict the development of this technology. Herein, one genetically multimodal treatment nanosystem (HES@PGEA/pKR-p53), composed of biocompatible hydroxyethyl starch (HES), low-toxic β-cyclodextrin-based ethanolamine-functionalized poly(glycidyl methacrylate) (CD-PGEA) and combined plasmid pKR-p53, is structurally designed based on host-guest assembly and electrostatic complexing. Supramolecular assembled HES@PGEA exhibits low cytotoxicity, excellent cellular internalization and enhanced gene transfection efficiency. With the delivery of pKR-p53, p53 and KillerRed proteins could be expressed simultaneously in the same tumor cell for p53-mediated apoptosis therapy and photodynamic therapy (PDT), where the synergistic effect of KillerRed and p53 proteins is achieved. Compared with single therapy, HES@PGEA/pKR-p53 shows more remarkable antitumor effects in the 4T1 tumor model.

The ability to appraise antibacterial potencies of surface-immobilized bactericidal polymers is still a major challenge in the engineering of antibacterial surfaces to combat hospital-acquired (nosocomial) infections. In this work, we fabricated a microfluidic platform with gradiently immobilized bactericidal polymers to enable the rapid appraisal of antibacterial potencies by in situ live/dead staining of bacteria. To this end, a variety of synthetic quaternary polymers, named QPEI-C1, QPEI-C6, QPEI-C8, and QPEI-C10, were gradiently immobilized in microfluidic channels, and their surface densities at different distances along the channels were quantified by using fluorescein-labeled polymers. We found that the surface densities of quaternary polymers could be well-tuned, and the length of the channel, resulting in a 50% reduction of live bacteria (L50), can be used to appraise the antibacterial potency of each bactericidal polymer. For instance, the L50 values of QPEI-C6-, QPEI-C8-, and QPEI-C10-modified channels against Escherichia coli were 35.5, 44.7, and 49.2 mm, respectively, indicating that QPEI-C10 exerted the most potent antibacterial efficacy. More importantly, this microfluidic platform enabled the rapid discrimination of antibacterial potencies of polymers (e.g., QPEI-C8, and QPEI-C10) while the conventional live/dead staining method found no significant difference. This work provides a powerful toolkit by combining advances of microfluidic systems and polymer science for the rapid screening of antibacterial coatings, which would find applications in surface modification of medical devices to combat bacterial infections.

Protein-based therapies are potential treatments for cancer, immunological, and cardiovascular diseases. However, effective delivery systems are needed because of their instability, immunogenicity, and so on. Crosslinked negatively charged heparin polysaccharide nanoparticle (HepNP) is proposed for protein delivery. HepNP can efficiently condense vascular endothelial growth factor (VEGF) because of the unique electronegative sulfonic acid and carboxyl domain of heparin. HepNP is then assembled with VEGF-C (Hep@VEGF-C) or VEGF-A (Hep@VEGF-A) protein for the therapy of myocardial infarction (MI) via intravenous (iv) injection. Hep@VEGF-A-mediated improvement of cardiac function by promoting angiogenesis is limited because of elevated vascular permeability, while Hep@VEGF-C effectively promotes lymphangiogenesis and reduces edema. On this basis, a graded delivery of VEGF-C (0.5-1 h post-MI) and VEGF-A (5 d post-MI) using HepNP is developed. At the dose ratio of 3:1 (Hep@VEGF-C vs Hep@VEGF-A), Hep@VEGF functional complexes substantially reduce the scar formation (≈-39%; p < 0.05) and improve cardiac function (≈+74%; p < 0.05). Such a HepNP delivery system provides a simple and effective therapeutic strategy for cardiovascular diseases by delivering functional proteins. Because of the unique binding ability of heparin with cytokines and growth factors, HepNP also has considerable application prospects in protein therapy for other serious diseases.

It is of great significance to develop biocompatible and degradable gene carriers with stimuli-enhanced gene therapy and imaging function. In this work, low-cytotoxic polycation PGEA (ethanolamine-functionalized poly(glycidyl methacrylate))-functionalized dextran-quantum dot (QD) nanohybrids (DQ-PGEA) were proposed as safe and efficient gene carriers via a facile and feasible method. The highly water-soluble dextran gives the carrier good stability, biocompatibility, and abundant modification sites, while QDs allow fluorescence (FL) imaging. Taking advantage of the pH-responsive self-destruction characteristic introduced by Schiff base linkages, DQ-PGEA nanohybrids could not only result in enhanced gene release but also contribute to the elimination of the carriers. Reduced (nondegradable) DQ-PGEA-R nanohybrids were also synthesized as counterparts to reveal the superiority of the responsive DQ-PGEA carriers. The effectiveness of the as-prepared gene delivery systems was verified adopting the antioncogene p53 in the mouse model of breast cancer. As expected, DQ-PGEA nanohybrids demonstrated a superior gene transfection performance and antitumor inhibition compared with their counterparts. Meanwhile, the gene delivery processes could be tracked in real time to visualize the therapeutic processes and realize FL imaging-guided gene therapy. The current multifunctional stimuli-responsive nanoplatforms with the self-destruction feature are intriguing candidates to achieve enhanced gene therapy for tumor treatment.

Cardiovascular and cerebrovascular ischemic diseases seriously affect human health. Endovascular stent placement is an effective treatment but always leads to in-stent restenosis (ISR). Gene-eluting stent, which combines gene therapy with stent implantation, is a potential method to prevent ISR. In this study, an efficient gene-eluting stent was designed on the basis of one new nucleic acid delivery system to decrease the possibility of ISR. The reduction-responsive branched nucleic acid vector (SKP) with low cytotoxicity was first synthesized via ring-opening reaction. The impressive in vitro transfection performances of SKP were proved using luciferase reporter, enhanced green fluorescent protein plasmid, and vascular endothelial growth factor plasmid (pVEGF). Subsequently, SKP/pVEGF complexes were coated on the surfaces of pretreated clinical stents to construct gene-eluting stents (S-SKP/pVEGF). Antirestenosis performance of S-SKP/pVEGF was evaluated via implanting stents into rabbit aortas. S-SKP/pVEGF could lead to the localized upregulation of VEGF proteins, improve the progress of re-endothelialization, and inhibit the development of ISR in vivo. Such efficient pVEGF-eluting stent with responsive nucleic acid delivery systems is very promising to prevent in-stent restenosis of cerebrovascular diseases.

A CRISPR/Cas9 system has emerged as a powerful tool for gene editing to treat genetic mutation related diseases. Due to the complete endothelial barrier, effective delivery of the CRISPR/Cas9 system to vasculatures remains a challenge for in vivo gene editing of genetic vascular diseases especially in aorta. Herein, it is reported that CHO‐PGEA (cholesterol (CHO)‐terminated ethanolamine‐aminated poly(glycidyl methacrylate)) with rich hydroxyl groups can deliver a plasmid based pCas9‐sgFbn1 system for the knockout of exon 10 in Fbn1 gene. This is the first report of a polycation‐mediated CRISPR/Cas9 system for gene editing in aorta of adult mice. CHO‐PGEA/pCas9‐sgFbn1 nanosystems can effectively contribute to the knockout of exon 10 in Fbn1 in vascular smooth muscle cells in vitro, which leads to the change of the phosphorylation of Smad2/3 and the increased expression of two downstream signals of Fbn1: Mmp‐2 and Ctgf. For in vivo application, the aortic enrichment of CHO‐PGEA/Cas9‐sgFbn1 is achieved by administering a pressor dose of angiotensin II (Ang II). The effects of the pCas9‐sgFbn1 system targeting Fbn1 demonstrate an increase in the expression of Mmp‐2 and Ctgf in aorta. Thus, the combination of CHO‐PGEA/pCas9‐sgFbn1 nanosystems with Ang II infusion can provide the possibility for in vivo gene editing in aorta.

Because of the abuse of antibiotics and threats of antibiotic resistance, bacterial infection is still one of the most difficult issues to be resolved. Thus, it is of great significance to explore novel antibacterial agents. In this paper, we investigated a type of silica-coated gold-silver nanocages (Au-Ag@SiO2 NCs) as antibacterial candidates. Their intrinsic characteristics of photothermal property and sustained release of Ag ions were fully exploited for near-infrared (NIR)-induced combined anti-infective therapy. The broad-spectrum antibacterial property of the as-prepared Au-Ag@SiO2 NCs was confirmed in vitro against Gram-positive Staphylococcus aureus ( S. aureus) and Gram-negative bacteria Escherichia coli ( E. coli). In addition, Au-Ag@SiO2 NCs exhibit effective treatment of the S. aureus biofilm with the assistance of NIR irradiation. More importantly, we assessed the in vivo antibacterial efficacy of Au-Ag@SiO2 NCs against S. aureus, which demonstrated sustainably enhanced therapeutic effects on a rat model with wound infection.

Growth factor delivery has attracted high attention for the treatment of severe skin wounds, while it is still desirable to develop new delivery systems with superiority for both antibacterial and delivery performances. In this work, one bifunctional nanosystem (HPT-RP) was constructed for the anti-bacterial and gene-delivery (plasmid encoding epidermal growth factor (EGF)) treatment of infected wound through the one-pot dual conjugation of photosensitizer and bacterium/cell-affinity phenylboronic acid onto hyperbranched polyaminoglycosides. HPT-RP realized high anti-bacterial ability owing to the receptor-mediated photodynamic therapy. The nanoparticle morphology and phenylboronic acid conjugation endowed HPT-RP with high gene transfection. In a rat infected-skin-defect model, HPT-RP exhibited the remarkable performance of anti-infective/EGF-delivery and accelerated healing. More importantly, a new sight into rat-EGF production revealed the underlying mechanism of extraneous EGF delivery and endogenous EGF production. This work sheds light on the rational design of growth factor delivery systems for infected wound therapy.

The cellular uptake process is critically influenced by the morphology of nanomaterials, which can further impact the therapeutic efficiency. Biodegradable and multifunctional nanomaterials with high cellular uptake efficiency and improved therapeutic effect are highly desirable. Herein, we report one-dimensional polycation-coated nanohybrids Fe3O4@Dex-PGEA (1D FDP) composed of polysaccharide dextran, Fe3O4 nanoparticles and low-toxic β-cyclodextrin-based ethanolamine-functionalized poly(glycidyl methacrylate) (CD-PGEA) via a facile self-assembly method, demonstrating excellent anticancer efficiency. Compared with spherical Fe3O4@Dex-PGEA (s-FDP) as the counterpart, 1D FDP demonstrates good cellular uptake efficiency, which can also rotate under an alternating magnetic field to generate a shear force to destroy tumor cells and exhibits excellent photothermal properties. Taking advantage of the highly efficient delivery, antioncogene p53-loaded 1D FDP nanoplatform shows the tri-modal gene/photothermal/magnetolytic synergistic anticancer effect in vitro and in vivo. Notably, the acidic tumor microenvironment-responsive biodegradation endows the 1D FDP nanohybrids with the capacity of efficient and rapid clearance in vivo, indicating their potential in biomedical application. Moreover, in vivo photothermal imaging and magnetic resonance imaging performance of 1D FDP for tumor accurate diagnosis are also evaluated. The multifunctional 1D FDP nanoplatform with pH-responsive degradability provides a promising candidate to realize enhanced gene/photothermal/magnetolytic therapy.

The development of new materials for fast and sensitive protease assay is in demand for timely diagnosis of diseases, such as cardiovascular disease, cancers, and Alzheimer disease. Herein, poly(methacrylic acid) (PMAA) brushes were synthesized from the surfaces of silica nanoparticles via surface-initiated atom transfer radical polymerization (ATRP), and functionalized with series of proteolytically cleavable peptides for highly sensitive protease assay. Upon the proteolytic cleavage of the peptides, a short peptide fragment with fluorescent tag (GGK-FITC) is released to the solution, which can be easily detected with a benchtop fluorescence microscope. The grafting densities of PMAA brushes and peptides can be readily tuned by controlling the monomer concentrations of sodium methacrylate in the ATRP reaction. Because of the three-dimensional architecture of PMAA brushes, the loading amount of peptides can reach 21.4% of the total weight of functionalized silica particles (22.4 peptides/nm2), which is mu...

Hepatocellular carcinoma (HCC) is one of the most common cancers. Maternally expressed gene 3 (MEG3, one kind of long noncoding RNA [lncRNA]) can act as a tumor suppressor and regulate P53 target gene expression. However, lncRNA MEG3 demonstrates relatively low or no expression in human HCC. This study provides a promising concept to codeliver lncRNA and pDNA for cancer therapy. As proof-of-concept, the pcDNA-MEG3 and pcDNA-P53 plasmids-condensed nanocomplexes with the liver-targeting polycation gene vector, pullulan-based ethanolamine-modified poly(glycidyl methacrylate) (denoted as PuPGEA), are proposed to codeliver lncRNA and pDNA to treat HCC. Pullulan-containing nanovectors are shown to be able to effectively mediate gene delivery in liver cells. To assess gene delivery performances of PuPGEA, a series of assays such as in vitro gene transfection, HCC cell proliferation, colony formation, migration, matrigel transwell assays, and in vivo xenograft animal models are carried out. The codelivery system with PuPGEA/(MEG3+P53) nanocomplexes demonstrates additive effects in suppressing HCC compared to PuPGEA/MEG3 or PuPGEA/P53 nanocomplexes alone. These results suggest that codelivery of lncRNA and pDNA by polycation nanovectors is a promising method to treat cancers.

Nucleic acid-based gene therapy is a promising treatment option to cure numerous intractable diseases. For non-viral gene carriers, low-molecular-weight polymeric vectors generally demonstrate poor transfection performance, but benefit their final removals from the body. Recently, it was reported that aminated poly(glycidyl methacrylate) (PGMA) is one potential gene vector. Based on ethylenediamine (ED)-functionalized low-molecular-weight PGMA (denoted by PGED), a flexible strategy was herein proposed to design new well-defined reducible cationic nanogels (denoted by PGED-NGs) with friendly crosslinking reagents for highly efficient nucleic acid delivery. α-Lipoic acid (LA), one natural antioxidant in human body, was readily introduced into ED-functionalized PGMA and crosslinked to produce cationic PGED-NGs with plentiful reducible lipoyl groups. PGED-NGs could effectively complex plasmid DNA (pDNA) and short interfering RNA (siRNA). Compared with pristine PGED, PGED-NGs exhibited much better performance of pDNA transfection. PGED-NGs also could efficiently transport MALAT1 siRNA (siR-M) into hepatoma cells and significantly suppressed the cancer cell proliferation and migration. The present work indicated that reducible cationic nanogels involving LA crosslinking reagents are one kind of competitive candidates for high-performance nucleic acid delivery systems. Statement of Significance Recently, the design of new types of high-performance nanoparticles is of great significance in delivering therapeutics. Nucleic acid-based therapy is a promising treatment option to cure numerous intractable diseases. A facile and straightforward strategy to fabricate safe nucleic acid delivery nanovectors is highly desirable. In this work, based on ethylenediamine-functionalized low-molecular-weight poly(glycidyl methacrylate), a flexible strategy was proposed to design new well-defined reducible cationic nanogels (denoted by PGED-NGs) with α-Lipoic acid, one friendly crosslinking reagent, for highly efficient nucleic acid delivery. Such PGED-NGs possess plentiful reducible lipoyl groups, effectively encapsulated pDNA and siRNA and exhibited excellent abilities of nucleic acid delivery. The present work indicated that reducible cationic nanogels involving α-lipoic acid crosslinking reagents are one kind of competitive candidates for high-performance nucleic acid delivery systems.

Organic/inorganic nanohybrids hold great importance in fabricating multifunctional theranostics to integrate therapeutic functions with real-time imaging. Although Au nanorods (NRs) have been employed for theranostics, complicated design of materials limits their practical applications. In this work, new multifunctional theranostic agents are designed and synthesized employing Au NRs with desirable near-infrared absorbance as the cores. A facile “grafting-onto” approach is put forward to prepare the series of hierarchical nanohybrids (Au-PGEA and Au-PGED) of Au NRs and poly(glycidyl methacrylate)-based polycations. The resultant nanohybrids can be utilized as gene carriers with high gene transfection performances. The structural effect of polycations on gene transfection is investigated in detail, and Au-PGEA with abundant hydroxyl groups on the surface exhibits superior performance. Au-PGEA nanohybrids are further validated to possess remarkable capability of combined photothermal therapy (PTT) and gene therapy (GT) for complementary tumor treatment. Moreover, significantly enhanced computed tomography (CT)/photoacoustic (PA) signals are detected both in vitro and in vivo, verifying the potential of Au-PGEA for dual-modal imaging with precise and accurate information. Therefore, these multifunctional nanohybrids fabricated from a simple and straightforward strategy are promising for in vivo dual-modal CT/PA imaging guided GT/PTT therapy with high antitumor efficacy.

Polysaccharide-based copolymers have attracted much attention due to their effective performances. Heparin, as a kind of polysaccharide with high negative charge densities, has attracted much attention in biomedical fields. In this work, we report a flexible way to adjust the solubility of heparin from water to oil via the introduction of tetrabutylammonium groups for further functionalization. A range of heparin-based comb copolymers with poly(poly(ethylene glycol) methyl ether methacrylate) (PPEGMEMA), poly(dimethylaminoethyl methacrylate) (PDMAEMA), or PPEGMEMA-b-PDMAEMA side chains were readily synthesized in a MeOH/dimethylsulfoxide mixture via atom-transfer radical polymerization. The heparin-based polymer nanoparticles involving cationic PDMAEMA were produced due to the electrostatic interaction between the negatively charged heparin backbone and PDMAEMA grafts. Then the pDNA condensation ability, cytotoxicity, and gene transfection efficiency of the nanoparticles were characterized in comparison with the reported gene vectors. The nanoparticles were proved to be effective gene vectors with low cytotoxicity and high transfection efficiency. This study demonstrates that by adjusting the solubility of heparin, polymer graft functionalization of heparin can be readily realized for wider applications.

It is very desirable to design multifunctional nanocomposites for theranostic applications via flexible strategies. The synthesis of one new multifunctional polycationic Au nanorod (NR)-coated Fe3 O4 nanosphere (NS) hierarchical nanocomposite (Au@pDM/Fe3 O4 ) based on the ternary assemblies of negatively charged Fe3 O4 cores (Fe3 O4 -PDA), polycation-modified Au nanorods (Au NR-pDM), and polycations is proposed. For such nanocomposites, the combined near-infrared absorbance properties of Fe3 O4 -PDA and Au NR-pDM are applied to photoacoustic imaging and photothermal therapy. Besides, Fe3 O4 and Au NR components allow the nanocomposites to serve as MRI and CT contrast agents. The prepared positively charged Au@pDM/Fe3 O4 also can complex plasmid DNA into pDNA/Au@pDM/Fe3 O4 and efficiently mediated gene therapy. The multifunctional applications of pDNA/Au@pDM/Fe3 O4 nanocomposites in trimodal imaging and combined photothermal/gene therapy are demonstrated using a xenografted rat glioma nude mouse model. The present study demonstrates that the proper assembly of different inorganic nanoparticles and polycations is an effective strategy to construct new multifunctional theranostic systems.

Supramolecular cyclodextrin polyrotaxane (PR) has attracted much attention due to their unique flexible properties. In this work, the reducible PR-based cationic block copolymer (SS-PR) was prepared via ATRP of DMAEMA based on the self-assembled pseudo-PR. A series of pseudo-comb polycations (SS-PR-pDM) with different molecular weights were subsequently produced via two-step ATRP of DMAEMA by using bromoisobutylryl-functionalized SS-PR as the macroinitiator. Incorporation of disulfide linkages in the backbone of PR permits the SS-PR and pseudo-comb SS-PR-pDM to be readily disassembled upon reductive stimuli. SS-PR-pDM exhibited the enhanced pDNA-condensing ability and similarly low toxicity compared with SS-PR. Meanwhile, SS-PR-pDM displayed higher cell internalization rates (88% for SS-PR-pDM3 vs. 77% for SS-PR) and luciferase gene transfection efficiency. The percentages of the EGFP-positive HeLa cells mediated by SS-PR-pDM3 and SS-PR were 44% and 22%, respectively. Furthermore, the favorable property of the pseudo-comb SS-PR-pDM benefited pDNA entering the nucleus. The present work demonstrates that properly grafting cationic side chains from reducible PR backbones via consecutive ATRP processes was one effective means to produce new PR-based supramolecular polycations. Statement of Significance Supramolecular cyclodextrin polyrotaxanes (PR) had been attracted much attention due to their unique flexible properties. In this work, two kinds of bioreducible PR-based polycations were synthesized via consecutive ATRP processes for gene delivery. The bioreducible PR-based cationic block copolymer (SS-PR) was prepared via ATRP of DMAEMA based on the self-assembled pseudopolyrotaxane of α-cyclodextrins (α-CD) with a disulfide-linked bromoisobutylryl-terminated PEG. Then, a series of pseudo-comb polycations (SS-PR-pDM) with different molecular weights were subsequently produced by using SS-PR-Br macroinitiators via step-two ATRP of DMAEMA. Incorporation of disulfide linkages in bromoisobutylryl-terminated PEG permits the SS-PR and pseudo-comb SS-PR-pDM to be readily disassembled upon reductive stimuli, contributing to gene delivery efficiency. SS-PR-pDM displayed higher cell internalization and gene transfection efficiency. In addtion, the favorable property of the pseudo-comb SS-PR-pDM benefited pDNA entering the nucleus. The present work demonstrates that properly grafting pDMAEMA side chains from bioreducible polyrotaxane backbones via consecutive ATPR processes was one effective means to produce new PR-based supramolecular polycations.

The unsymmetrical morphology and unique properties of Janus nanoparticles (JNPs) provide superior performances for biomedical applications. In this work, a general and facile strategy is developed to construct a series of symmetrical and unsymmetrical chitosan/gold nanoparticles. Taking advantage of the active motion derived from Janus structure, selective surface functionalization of polysaccharide domain, and photothermal effect of gold nanorods, Janus chitosan/gold nanoparticles (J-Au-CS) are selected as a model system to construct Janus-structured chitosan/gold nanohybrids (J-ACP). Near-infrared (NIR)-responsive J-ACP composed of polycationic chitosan nanospheres and PEGylated gold nanorods hold great potential to realize photoacoustic (PA) imaging-guided complementary photothermal therapy (PTT)/gene therapy for breast cancer. The morphology effect of chitosan/gold nanostructures on enhanced PTT, cellular uptake, and gene transfection is investigated. The feasibility of PA imaging to track the accumulation of J-ACP and guide PTT is also explored. Notably, synergistic therapy is achieved based on PTT-enhanced gene therapy. In addition, the loading function of chitosan/gold nanoparticles for fluorescence imaging is demonstrated. The current work extends the application of JNPs for imaging-guided synergistic cancer therapy and provides flexible candidates with distinct structures for diverse biomedical applications.

Left ventricular hypertrophy and fibrosis are major risk factors for heart failure, which require timely and effective treatment. Genetic therapy has been shown to ameliorate hypertrophic cardiac damage. In this study, it is found that in mice, the dopamine D5 receptor (D5R) expression in the left ventricle (LV) progressively decreases with worsening of transverse aortic constriction‐induced left ventricular hypertrophy. Then, a reversible treatment of left ventricular hypertrophy with Drd5 nucleic acids delivered by tobramycin‐based hyperbranched polyaminoglycoside (SS‐HPT) is studied. The heart‐specific increase in D5R expression by SS‐HPT/Drd5 plasmid in the early stage of left ventricular hypertrophy attenuates cardiac hypertrophy and fibrosis by preventing oxidative and endoplasmic reticulum (ER) stress and ameliorating autophagic dysregulation. By contrast, SS‐HPT/Drd5 siRNA promotes the progression of left ventricular hypertrophy and accelerates the deterioration of myocardial function into heart failure. The reduction in cardiac D5R expression and dysregulated autophagy are observed in patients with hypertrophic cardiomyopathy and heart failure. The data show a cardiac‐specific beneficial effect of SS‐HPT/Drd5 plasmid on myocardial remodeling and dysfunction, which may provide an effective therapy of patients with left ventricular hypertrophy and heart failure.

Implantable medical devices are widely used, but biomaterial-associated infections (BAIs) impose a huge economic burden and increase the mortality of patients. Therefore, BAIs are a serious concern that must be urgently resolved. Materials with antibacterial properties have become hotspots of current research and development. In the present work, quaternized chitosan (QCS) is used as an antibacterial agent and blended with thermoplastic polyurethane (TPU) to create an antibacterial material for tracheal intubation tubes. The modified TPU material (QCS-TPU) exhibited good mechanical properties and excellent long-term antibacterial performance. Under in vitro hydrodynamic conditions, QCS-TPU retained its strong antibacterial properties. QCS-TPU also possessed a low hemolysis rate and cytotoxicity. The current work is expected to provide a facile and feasible strategy for the preparation of antibacterial catheters and aid in the discovery of promising clinical applications to prevent BAIs.

Nowadays, nucleic acid therapy has become a promising way for the treatment of various malignant diseases. Cyclodextrin (CD)-based nucleic acid delivery systems have attracted widespread attention due to the favorable chemical structures and excellent biological properties of CD. Recently, a variety of CD-based nucleic acid delivery systems has been designed according to the different functions of CD for flexible gene therapies. In this review, the construction strategies and biomedical applications of CD-based nucleic acid delivery systems are mainly focused on. The review begins with an introduction to the synthesis and properties of simple CD-grafted polycations. Thereafter, CD-related supramolecular assemblies based on different guest components are discussed in detail. Finally, different CD-based organic/inorganic nanohybrids and their relevant functions are demonstrated. It is hoped that this brief review will motivate the delicate design of CD-based nucleic acid delivery systems for potential clinical applications.

Self-assembly of gold nanoparticles demonstrates a promising approach to realize enhanced photoacoustic imaging (PAI) and photothermal therapy (PTT) for accurate diagnosis and efficient cancer therapy. Herein, unique photothermal assemblies with tunable patterns of gold nanoparticles (including arcs, rings, ribbons, and vesicles) on poly(lactic-co-glycolic acid) (PLGA) spheres are constructed taking advantage of emulsion-confined and polymer-directed self-assembly strategies. The influencing factors and formation mechanism to produce the assemblies are investigated in details. Both the emulsion structure and migration behaviors of amphiphilic block copolymer tethered gold nanoparticles are found to contribute to the formation of versatile photothermal assemblies. Hyaluronic acid-modified R-PLGA-Au (RPA) exhibits outstanding photothermal performances under NIR laser irradiation, which is induced by strong plasmonic coupling between adjacent gold nanoparticles. It is interesting that secondary assembly of RPA can be triggered by NIR laser irradiation. Prolonged residence time in tumors is achieved after RPA assemblies are fused into superstructures with larger sizes, realizing real-time monitoring of the therapeutic processes via PAI with enhanced photoacoustic signals. Notably, synergistic effect resulting from PTT-enhanced chemotherapy is realized to demonstrate high antitumor performance. This work provides a facile strategy to construct flexible photothermal assemblies with favorable properties for imaging-guided synergistic therapy.