Supramolecular Adhesive Hydrogels for Tissue Engineering Applications.

Tissue engineering is a promising and revolutionary strategy to treat patients who suffer the loss or failure of an organ or tissue, with the aim to restore the dysfunctional tissues and enhance life expectancy. Supramolecular adhesive hydrogels are emerging as appealing materials for tissue engineering applications owing to their favorable attributes such as tailorable structure, inherent flexibility, excellent biocompatibility, near-physiological environment, dynamic mechanical strength, and particularly attractive self-adhesiveness. In this review, the key design principles and various supramolecular strategies to construct adhesive hydrogels are comprehensively summarized. Thereafter, the recent research progress regarding their tissue engineering applications, including primarily dermal tissue repair, muscle tissue repair, bone tissue repair, neural tissue repair, vascular tissue repair, oral tissue repair, corneal tissue repair, cardiac tissue repair, fetal membrane repair, hepatic tissue repair, and gastric tissue repair, is systematically highlighted. Finally, the scientific challenges and the remaining opportunities are underlined to show a full picture of the supramolecular adhesive hydrogels. This review is expected to offer comparative views and critical insights to inspire more advanced studies on supramolecular adhesive hydrogels and pave the way for different fields even beyond tissue engineering applications.

Long-Lived Organic Room-Temperature Phosphorescence from Amorphous Polymer Systems.

Long-lived organic room-temperature phosphorescence (RTP) materials have recently drawn extensive attention because of their promising applications in information security, biological imaging, optoelectronic devices, and intelligent sensors. In contrast to conventional fluorescence, the RTP phenomenon originates from the slow radiative transition of triplet excitons. Thus, enhancing the intersystem crossing (ISC) rate from the lowest excited singlet state (S1) to the excited triplet state and suppressing the nonradiative relaxation channels of the lowest excited triplet state (T1) are reasonable methods for realizing highly efficient RTP in purely organic materials. Over the past few decades, many strategies have been designed on the basis of the above two crucial factors. The introduction of heavy atoms, aromatic carbonyl groups, and other heteroatoms with abundant lone-pair electrons has been demonstrated to strengthen the spin-orbit coupling, thereby successfully facilitating the ISC process. Furthermore, the rigid environment is commonly constructed through crystal engineering to restrict intramolecular motions and intermolecular collisions to decrease excited-state energy dissipation. However, most crystal-based organic RTP materials suffer from poor processability, flexibility, and reproducibility, becoming a thorny obstacle to their practical application.Amorphous organic polymers with long-lived RTP characteristics are more competitive in materials science. The intertwined structures and long chains of polymers not only ensure the rigid environment with multiple interactions but also protect triplet excitons from the surroundings, which are conducive to realizing ultralong and bright RTP emission. Exploring the fabrication strategies, intrinsic mechanisms, and practical applications of organic long-lived RTP polymers is highly desirable but remains a formidable challenge. In particular, intelligent organic RTP polymer systems that are capable of dynamically responding to external stimuli (e.g., light, temperature, oxygen, and humidity) have been rarely reported. To develop multifunctional RTP materials and expand their potential applications, a great amount of effort has been expended.This Account gives a summary of the significant advances in amorphous organic RTP polymer systems, especially smart stimulus-responsive ones, focusing on the construction of a rigid environment to suppress nonradiative deactivation by abundant inter/intramolecular interactions. The typical interactions in RTP polymer systems mainly include hydrogen bonding, ionic bonding, and covalent bonding, which can change the molecular electronic structures and affect the energy dissipation channels of the excited states. An in-depth understanding of intrinsic mechanisms and an extensive exploration of potential applications for excitation-dependent color-tunable, ultraviolet (UV) irradiation-activated, temperature-dependent, water-responsive, and circularly polarized RTP polymer systems are distinctly illustrated in this Account. Furthermore, we propose some detailed perspectives in terms of materials design, mechanism exploration, and promising application potential with the hope to provide helpful guidance for the future development of amorphous organic RTP polymers.

pH-Responsive Polymeric Micelle Dynamic Complexes for Selective Killing of Helicobacter pylori.

Helicobacter pylori, the world's most common chronic infection-causing pathogen, is responsible for causing gastric ulcers, the fourth-leading cause of cancer-related death globally in 2020. In recent years, the effectiveness of the current treatment regimen (two antibiotics and one proton pump inhibitor) has often been plagued with problems such as resistance and the undesired elimination of commensal bacteria. Herein, we report the synthesis of block and random copolycarbonates, functionalized with cationic guanidinium and anionic acetate functional groups, aimed at selectively killing H. pylori in the acidic environment of the stomach, while remaining nontoxic to the commensal bacteria in the gut. The compositions of the polymers were fine-tuned so that the polymers were readily dispersed in water without any difficulty at both pH 3.0 and 7.4. The self-assembly behavior of the polymers at different pH values by dynamic light scattering showed that the random and block copolymers formed stable micelles in a simulated gastric environment (pH 3.0) while aggregated at pH 7.4. Both polymers demonstrated stronger antibacterial activity against H. pylori than the guanidinium-functionalized homopolymer without any acetate functional group at pH 3.0. The block copolymer was significantly more bactericidal at pH 3.0 across the concentrations tested, as compared to the random copolymer, while it did not show significant toxicity toward rat red blood cells (rRBCs) and HK-2 cells or bactericidal effect toward E. coli (a common gut bacterium) and nor caused aggregation of rRBCs at its effective concentration and at physiological pH of 7.4. Additionally, both the block and random copolymers were much more stable against hydrolysis at pH 3.0 than at pH 7.4. This study provides insight into the influence of both polymer architecture and dynamic assembly on the bioactivities of antimicrobial polymers, where the disassembly of coacervates into narrowly dispersed micelles at pH 3 make them potent antimicrobials aided by the protonated carboxylic acid block.

Four-in-One Stimulus-Responsive Long-Lived Luminescent Systems Based on Pyrene-Doped Amorphous Polymers.

Materials exhibiting ultralong luminescent lifetime show promising applications in the fields of information encryption, sensing, and bioimaging. Herein, we present a low-cost and general strategy to achieve stimulus-responsive ultralong organic phosphorescence (UOP) based on pyrene chromophores doped into polymer matrices. The UOP of the resulted systems presents radiation-, concentration-, time-, and excitation-dependent characteristics. The UOP color can be turned from blue to red by changing the excitation wavelength or the concentration of chromophores. Experimental results prove that these characteristics are attributed to the consumption of triplet oxygen and the different aggregation states of chromophores in the polymer matrices. Finally, we demonstrate that these systems could be applied for multilevel information encryption. This work would promote further development of multi-responsive long-lived luminescent materials.

NIR-Actuated Remote Activation of Ferroptosis in Target Tumor Cells through a Photothermally Responsive Iron-Chelated Biopolymer Nanoplatform.

Ferroptosis is a new form of regulated cell death that shows promise for tumor treatment. Most current ferroptosis tumor therapies are based on the intrinsic pathological features of the malignancies, and it would be of clinical significance to develop ferroptosis-inducing strategies with improved tumor specificity and modulability. Here we report a polydopamine-based nanoplatform (FeII PDA@LAP-PEG-cRGD) for the efficient loading of Fe2+ and ß-lapachone (LAP), which could readily initiate ferroptosis in tumor cells upon treatment with near-infrared light. PDA nanostructures could generate mild hyperthermia under NIR irritation and trigger the release of the ferroptosis-inducing Fe2+ ions. The NIR-actuated photothermal effect would also activate cellular heat shock response and upregulate the downstream NQO1 via HSP70/NQO1 axis to facilitate bioreduction of the concurrently released ß-lapachone and enhance intracellular H2 O2 formation to promote the Fe2+ -mediated lipid peroxidation.

Redox and pH Dual Responsive Polymer Based Nanoparticles for In Vivo Drug Delivery.

Responsive nanomaterials have emerged as promising candidates as drug delivery vehicles in order to address biomedical diseases such as cancer. In this work, polymer-based responsive nanoparticles prepared by a supramolecular approach are loaded with doxorubicin (DOX) for the cancer therapy. The nanoparticles contain disulfide bonds within the polymer network, allowing the release of the DOX payload in a reducing environment within the endoplasm of cancer cells. In addition, the loaded drug can also be released under acidic environment. In vitro anticancer studies using redox and pH dual responsive nanoparticles show excellent performance in inducing cell death and apoptosis. Zebrafish larvae treated with DOX-loaded nanoparticles exhibit an improved viability as compared with the cases treated with free DOX by the end of a 3 d treatment. Confocal imaging is utilized to provide the daily assessment of tumor size on zebrafish larva models treated with DOX-loaded nanoparticles, presenting sustainable reduction of tumor. This work demonstrates the development of functional nanoparticles with dual responsive properties for both in vitro and in vivo drug delivery in the cancer therapy.

Hybrid Nanoparticles as Drug Carriers for Controlled Chemotherapy of Cancer.

Rapid developments in materials science and biological mechanisms have greatly boosted the research discoveries of new drug delivery systems. In the past few decades, hundreds of nanoparticle-based drug carriers have been reported almost on a daily basis, in which new materials, structures, and mechanisms are proposed and evaluated. Standing out among the drug carriers, the hybrid nanoparticle systems offer a great opportunity for the optimization and improvement of conventional chemotherapy. By combining several features of functional components, these hybrid nanoparticles have shown excellent promises of improved biosafety, biocompatibility, multifunctionality, biodegradability, and so forth. In this Personal Account, we highlight the recent research advances of some representative hybrid nanoparticles as drug delivery systems and discuss their design strategies and responsive mechanisms for controlled drug delivery.

Synergistic Assembly of Covalent and Supramolecular Polymers.

Integrating irreplaceable features of both covalent chemistry and noncovalent interactions into a single entity to maximize the applicability is highly desired. Here, a discovery of this type of hybrid, developed by Stupp and co-workers, is developed, where a synergistic combination of covalent and noncovalent compartments enables them to assemble by each other perfectively. The covalent compartments can grow into polymer chains assisted by a supramolecular compartment. The supramolecular compartments can be reversibly removed and re-formed to reconstitute the hybrid structure. The obtained soft materials can serve as functional platforms for molecular delivery or self-repairing materials.

Recent advances in biocompatible nanocarriers for delivery of chemotherapeutic cargoes towards cancer therapy.

Cancer is currently one of the major diseases that has gained a lot of scientific attention. Conventional cancer therapeutics involve surgical removal of tumors from patients followed by chemotherapeutic treatment. In the use of anticancer drugs during the chemotherapy process, patients often suffer from a variety of undesirable side effects including damage to normal organs. Thus, there is an urgent need for the development of novel strategies to overcome these side effect issues. Among several strategies, the utilization of nanocarriers for anticancer drug delivery has shown improved therapeutic efficiency of the drugs with minimization of the undesirable side effects. In this review, we discuss various types of nanocarriers recently reported in the literature for application in cancer therapy. We introduce some targeting ligands that have been functionalized on nanocarriers in order to impart specificity to the nanocarriers for targeted drug delivery. We also highlight some therapeutic cargoes that are commonly used and their therapeutic mechanisms in cancer treatment. Finally, we summarize some interesting stimulus strategies for controlled release of therapeutic cargoes at tumor sites. This review is expected to inspire new ideas and create novel strategies in advancing efficient cancer therapy using nanomedicine approaches.

Pluronic-poly (acrylic acid)-cysteine/Pluronic L121 mixed micelles improve the oral bioavailability of paclitaxel.

The aim of the study is to synthesize a thiolated Pluronic copolymer, Pluronic-poly (acrylic acid)-cysteine copolymer, to construct a mixed micelle system with the Pluronic-poly (acrylic acid)-cysteine copolymer and Pluronic L121 (PL121) and to evaluate the potential of these mixed micelles as an oral drug delivery system for paclitaxel. Compared with Pluronic-poly (acrylic acid)-cysteine micelles, drug-loading capacity of Pluronic-poly (acrylic acid)-cysteine/PL121 mixed micelles was increased from 0.4 to 2.87%. In vitro release test indicated that Pluronic-poly (acrylic acid)-cysteine/PL121 mixed micelles exhibited a pH sensitivity. The permeability of drug-loaded micelles in the intestinal tract was studied with an in situ perfusion method in rats. The presence of verapamil and Pluronic both improved the intestinal permeability of paclitaxel, which further certified the inhibition effect of thiolated Pluronic on P-gp. In pharmacokinetic study, the area under the plasma concentration-time curve (AUC0→∞) of paclitaxel-loaded mixed micelles was four times greater than that of the paclitaxel solution (p < 0.05). In general, Pluronic-poly (acrylic acid)-cysteine/PL121 micelles were proven to be a potential oral drug delivery system for paclitaxel.

In Situ Mitochondrial Biomineralization for Drug-Free Cancer Therapy.

The common clinical chemotherapy often brings serious side effects to patients, mainly due to the off-target and leakage of toxic drugs. However, this is fatal for some specific clinical tumors, such as brain tumors and neuroma. This study performs a drug-free approach by encapsulating black phosphorus (BP) and calcium peroxide (CaO2) in liposomes with surface-modified triphenylphosphonium (BCLT) to develop mitochondria targeting calcification for cancer therapy without damaging normal cells. BCLT preferentially accumulates inside tumor mitochondria and then is activated by near-infrared (NIR) laser irradiation to produce abundant PO4 3- and Ca2+ to accelerate in situ mitochondrial mineralization, leading to mitochondrial dysfunction and cancer cell death. More importantly, both PO4 3- and Ca2+ are essential components of metabolism in the body, and random gradient diffusion or premature leakage does not cause damage to adjacent normal cells. This achievement promises to be an alternative to conventional chemotherapy in clinical practice for many specific tumor types.

Synthesis and chirality control of bulk crystals and nanocrystals: from a right-handed nonpolar chain to a left-handed polar chain.

Both bulk crystals and nanocrystals of two helical complexes, [Cu(µ2-L)(H2O)]n (1) and {[Cu(µ2-L)(H2O)]·2H2O}n (2) (H2L = thiazolidine-2,4-dicarboxylic acid), have been synthesized with the chiralities of right-handedness (1) and left-handedness (2), respectively. 4-Cyanopyridine and poly(vinylpyrrolidone) (PVP) have been applied to control the synthesis of complexes with different helicities in bulk-crystal and nanocrystal forms, respectively. 2 can be irreversibly transformed to 1 under heating. Associated with the conformation changing, the symmetry alters between nonpolar and polar space groups.

Metal-Organic Frameworks Meet Polymers: From Synthesis Strategies to Healthcare Applications.

Metal-organic frameworks (MOFs) have been at the forefront of nanotechnological research for the past decade owing to their high porosity, high surface area, diverse configurations, and controllable chemical structures. They are a rapidly developing class of nanomaterials that are predominantly applied in batteries, supercapacitors, electrocatalysis, photocatalysis, sensors, drug delivery, gas separation, adsorption, and storage. However, the limited functions and unsatisfactory performance of MOFs resulting from their low chemical and mechanical stability hamper further development. Hybridizing MOFs with polymers is an excellent solution to these problems, because polymers-which are soft, flexible, malleable, and processable-can induce unique properties in the hybrids based on those of the two disparate components while retaining their individuality. This review highlights recent advances in the preparation of MOF-polymer nanomaterials. Furthermore, several applications wherein the incorporation of polymers enhances the MOF performance are discussed, such as anticancer therapy, bacterial elimination, imaging, therapeutics, protection from oxidative stress and inflammation, and environmental remediation. Finally, insights from the focus of existing research and design principles for mitigating future challenges are presented.

Nanocompartment-confined polymerization in living systems.

Polymerization in living systems has become an effective strategy to regulate cell functions and behavior. However, the requirement of high concentrations of monomers, the existence of complicated intracorporal interferences, and the demand for extra external stimulations hinder their further biological applications. Herein, a nanocompartment-confined strategy that provides a confined and secluded environment for monomer enrichment and isolation is developed to achieve high polymerization efficiency, reduce the interference from external environment, and realize broad-spectrum polymerizations in living systems. For exogenous photopolymerization, the light-mediated free-radical polymerization of sodium 4-styrenesulfonate induces a 2.7-fold increase in the reaction rate with the protection of a confined environment. For endogenous hydrogen peroxide-responsive polymerization, p­aminodiphenylamine hydrochloride embedded in a nanocompartment not only performs a 6.4-fold higher reaction rate than that of free monomers, but also activates an effective second near-infrared photoacoustic imaging-guided photothermal immunotherapy at tumor sites. This nanocompartment-confined strategy breaks the shackles of conventional polymerization, providing a universal platform for in vivo synthesis of polymers with diverse structures and functions.

Graphene oxide wrapping on squaraine-loaded mesoporous silica nanoparticles for bioimaging.

Squaraine dyes were loaded inside mesoporous silica nanoparticles, and the nanoparticle surfaces were then wrapped with ultrathin graphene oxide sheets, leading to the formation of a novel hybrid material. The hybrid exhibits remarkable stability and can efficiently protect the loaded dye from nucleophilic attack. The biocompatible hybrid is noncytotoxic and presents significant potential for application in fluorescence imaging in vitro.

Effects of Hydrophobicity on Antimicrobial Activity, Selectivity, and Functional Mechanism of Guanidinium-Functionalized Polymers.

In this study, a series of guanidinium-functionalized polycarbonate random co-polymers is prepared from organocatalytic ring-opening polymerization to investigate the effect of the hydrophobic side chain (ethyl, propyl, isopropyl, benzyl, and hexyl) on their antimicrobial activity and selectivity. Although the polymers exhibit similar minimum inhibitory concentrations, the more hydrophobic polymers exhibit a faster rate of bacteria elimination. At higher percentage content (20 mol%), polymers with more hydrophobic side chains suffer from poor selectivity due to their high hemolytic activity. The highly hydrophobic co-polymer, containing the hydrophobic hexyl-functionalized cyclic carbonate, kills bacteria via a membrane-disruptive mechanism. Micelle formation leads to a lower extent of membrane disruption. This study unravels the effects of hydrophobic side chains on the activities of the polymers and their killing mechanism, providing insights into the design of new antimicrobial polymers.

Polarization of Tumor-Associated Macrophages Promoted by Vitamin C-Loaded Liposomes for Cancer Immunotherapy.

While checkpoint blockade immunotherapy as a promising clinical modality has revolutionized cancer treatment, it is of benefit to only a subset of patients because of the tumor immunosuppressive microenvironment. Herein, we report that the specified delivery of vitamin C at the tumor site by responsive lipid nanoparticles can efficiently induce oxidative toxicity and the polarization of M1 macrophages, promoting the infiltration of activating cytotoxic T lymphocytes in the tumor microenvironment for intensive immune checkpoint blocking therapy. Both in vitro and in vivo assays demonstrate successful vitamin C-induced polarization of M2 macrophages to M1 macrophages. In vivo transcriptome analysis also reveals the activation mechanism of vitamin C immunity. More importantly, the combination approach displays much better immune response and immune process within the tumor microenvironment than clinical programmed cell death ligand 1 (Anti-PD-L1) alone. This work provides a powerful therapeutic application of vitamin C to amplify Anti-PD-L1 immunotherapy in cancer treatment, which brings hope to patients with clinically insensitive immunity.

Elucidating the anticancer activities of guanidinium-functionalized amphiphilic random copolymers by varying the structure and composition in the hydrophobic monomer.

Rationale: Use of traditional anticancer chemotherapeutics has been hindered by the multifactorial nature of multi-drug resistance (MDR) development and metastasis. Recently, cationic polycarbonates were reported as novel unconventional anticancer agents that mitigated MDR and inhibited metastasis. The aim of this study is to explore structure-anticancer activity relationship. Specifically, a series of cationic guanidinium-based random copolymers of varying hydrophobicity was synthesized with a narrow polydispersity (Ð = 1.12-1.27) via organocatalytic ring-opening polymerization (OROP) of functional cyclic carbonate monomers, and evaluated for anticancer activity, killing kinetics, degradability and functional mechanism. Methods: Linear, branched and aromatic hydrophobic side chain units, such as ethyl, benzyl, butyl, isobutyl and hexyl moieties were explored as comonomer units for modulating anticancer activity. As hydrophobicity/hydrophilicity balance of the polymers determines their anticancer efficacy, the feed ratio between the two monomers was varied to tune their hydrophobicity. Results: Notably, incorporating the hexyl moiety greatly enhanced anticancer efficiency and killing kinetics on cancer cells. Degradation studies showed that the polymers degraded completely within 4-6 days. Flow cytometry and lactate dehydrogenase (LDH) release analyses demonstrated that anticancer mechanism of the copolymers containing a hydrophobic co-monomer was concentration dependent, apoptosis at IC50, and both apoptosis and necrosis at 2 × IC50. In contrast, the homopolymer without a hydrophobic comonomer killed cancer cells predominantly via apoptotic mechanism. Conclusion: The hydrophobicity of the polymers played an important role in anticancer efficacy, killing kinetics and anticancer mechanism. This study provides valuable insights into designing novel anticancer agents utilizing polymers.

Ultrasmall Alloy Nanozyme for Ultrasound- and Near-Infrared Light-Promoted Tumor Ablation.

The therapeutic effect of chemodynamic therapy (CDT) is significantly restricted by the stern reaction conditions and slow reaction rate of the Fenton reaction (pH 3-4). Herein, we report an ultrasmall trimetallic (Pd, Cu, and Fe) alloy nanozyme (PCF-a NEs) possessing dynamic active-site synergism, thus exhibiting a cascade glutathione peroxidase and peroxidase (POD) mimicking activities in circumneutral pH. PCF-a NEs exhibit photothermally augmented POD property and high photothermal conversion efficiency (62%) for synergistic tumor cell apoptosis. In addition, ultrasound can also enhance the mass transfer at active catalytic sites of PCF-a NEs, in turn accelerating Fenton-like reaction for tumor-specific CDT. This work provides a strategy for engineering alloy nanozymes in a bioinspired way for the amplification of intratumor reactive oxygen species in response to external stimuli, demonstrating enhanced efficiency for the inhibition of tumor growth in vitro and in vivo.

Self-assembled semiconducting polymer based hybrid nanoagents for synergistic tumor treatment.

There is an impending need for the development of carrier-free nanosystems for single laser triggered activation of phototherapy, as such approach can overcome the drawbacks associated with irradiation by two distinct laser sources for avoiding prolonged treatment time and complex treatment protocols. Herein, we developed a self-assembled nanosystem (SCP-CS) consisting of a new semiconducting polymer (SCP) and encapsulated ultrasmall CuS (CS) nanoparticles. The SCP component displays remarkable near infrared (NIR) induced photothermal ability, enhanced reactive oxygen species (ROS) generation, and incredible photoacoustic (PA) signals upon activation by 808 nm laser for phototherapy mediated cancer ablation. The CuS component improves the PA imaging ability of SCP-CS, and also enhances photo-induced chemodynamic efficacy. Attributed to promoted single laser-triggered hyperthermia and enhanced ROS generation, the SCP-CS nanosystem shows effective intracellular uptake and intratumoral accumulation, enhanced tumor suppression with reduced treatment time, and devoid of any noticeable toxicity.