Combined activation of artificial and natural ion channels for disrupting mitochondrial ion homeostasis towards effective postoperative tumor recurrence and metastasis suppression.

Rationale: Pharmacological targeting of mitochondrial ion channels is developing as a new direction in cancer therapy. The opening or closing of these channels can impact mitochondrial function and structure by interfering with intracellular ion homeostasis, thereby regulating cell fate. Nevertheless, their abnormal expression or regulation poses challenges in eliminating cancer cells, and further contributes to metastasis, recurrence, and drug resistance. Methods: We developed an engineered mitochondrial targeted delivery system with self-reinforcing potassium ion (K+) influx via amphiphilic mitochondrial targeting polymer (TMP) as carriers to co-deliver natural K+ channel agonists (Dinitrogen oxide, DZX) and artificial K+ channel molecules (5F8). Results: Using this method, DZX specifically activated natural K+ channels, whereas 5F8 assembled artificial K+ channels on the mitochondrial membrane, leading to mitochondrial K+ influx, as well as oxidative stress and activation of the mitochondrial apoptotic pathway. Conclusion: The synergistic effect of 5F8 and DZX presents greater effectiveness in killing cancer cells than DZX alone, and effectively inhibited tumor recurrence and lung metastasis following surgical resection of breast cancer tumors in animal models. This strategy innovatively integrates antihypertensive drugs with artificial ion channel molecules for the first time to effectively inhibit tumor recurrence and metastasis by disrupting intracellular ion homeostasis, which will provide a novel perspective for postoperative tumor therapy.

Recent advances in biomaterial designs for assisting CAR-T cell therapy towards potential solid tumor treatment.

Chimeric antigen receptor T (CAR-T) cells have shown promising outcomes in the treatment of hematologic malignancies. However, CAR-T cell therapy in solid tumor treatment has been significantly hindered, due to the complex manufacturing process, difficulties in proliferation and infiltration, lack of precision, or poor visualization ability. Fortunately, recent reports have shown that functional biomaterial designs such as nanoparticles, polymers, hydrogels, or implantable scaffolds might have potential to address the above challenges. In this review, we aim to summarize the recent advances in the designs of functional biomaterials for assisting CAR-T cell therapy for potential solid tumor treatments. Firstly, by enabling efficient CAR gene delivery in vivo and in vitro, functional biomaterials can streamline the difficult process of CAR-T cell therapy manufacturing. Secondly, they might also serve as carriers for drugs and bioactive molecules, promoting the proliferation and infiltration of CAR-T cells. Furthermore, a number of functional biomaterial designs with immunomodulatory properties might modulate the tumor microenvironment, which could provide a platform for combination therapies or improve the efficacy of CAR-T cell therapy through synergistic therapeutic effects. Last but not least, the current challenges with biomaterials-based CAR-T therapies will also be discussed, which might be helpful for the future design of CAR-T therapy in solid tumor treatment.

Mitochondrial Artificial K+ Channel Construction Using MPTPP@5F8 Nanoparticles for Overcoming Cancer Drug Resistance via Disrupting Cellular Ion Homeostasis.

Mitochondrial potassium ion channels have become a promising target for cancer therapy. However, in malignant tumors, their low expression or inhibitory regulation typically leads to undesired cancer therapy, or even induces drug resistance. Herein, this work develops an in situ mitochondria-targeted artificial K+ channel construction strategy, with the purpose to trigger cancer cell apoptosis by impairing mitochondrial ion homeostasis. Considering the fact that cancer cells have a lower membrane potential than that of normal cells, this strategy can selectively deliver artificial K+ channel molecule 5F8 to the mitochondria of cancer cells, by using a mitochondria-targeting triphenylphosphine (TPP) modified block polymer (MPTPP) as a carrier. More importantly, 5F8 can further specifically form a K+ -selective ion channel through the directional assembly of crown ethers on the mitochondrial membrane, thereby inducing mitochondrial K+ influx and disrupting ions homeostasis. Thanks to this design, mitochondrial dysfunction, including decreased mitochondrial membrane potential, reduced adenosine triphosphate (ATP) synthesis, downregulated antiapoptotic BCL-2 and MCL-1 protein levels, and increased reactive oxygen species (ROS) levels, can further effectively induce the programmed apoptosis of multidrug-resistant cancer cells, no matter in case of pump or nonpump dependent drug resistance. In short, this mitochondria-targeted artificial K+ -selective ion channel construction strategy may be beneficial for potential drug resistance cancer therapy.

Injectable Supramolecular Hydrogels for In Situ Programming of Car-T Cells toward Solid Tumor Immunotherapy.

Chimeric antigen receptor (CAR)-T cell immunotherapy is approved in the treatment of hematological malignancies, but remains far from satisfactory in solid tumor treatment due to inadequate intra-tumor CAR-T cell infiltration. Herein, an injectable supramolecular hydrogel system, based on self-assembly between cationic polymer mPEG-PCL-PEI (PPP) conjugated with T cell targeting anti-CD3e f(ab')2 fragment and α-cyclodextrin (α-CD), is designed to load plasmid CAR (pCAR) with a T cell specific CD2 promoter, which successfully achieves in situ fabrication and effective accumulation of CAR-T cells at the tumor site in humanized mice models. More importantly, due to this tumor microenvironment reprogramming, secretion of cellular inflammatory cytokines (interleukin-2 (IL-2), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ)) or tumor killer protein granzyme B is significantly promoted, which reverses the immunosuppressive microenvironment and significantly enhances the intra-tumor CAR-T cells and cytotoxic T cells infiltration. To the best of the current knowledge, this is a pioneer report of using injectable supramolecular hydrogel for in situ reprogramming CAR-T cells, which might be beneficial for solid tumor CAR-T immunotherapy.

Research advances in smart responsive-hydrogel dressings with potential clinical diabetic wound healing properties.

The treatment of chronic and non-healing wounds in diabetic patients remains a major medical problem. Recent reports have shown that hydrogel wound dressings might be an effective strategy for treating diabetic wounds due to their excellent hydrophilicity, good drug-loading ability and sustained drug release properties. As a typical example, hyaluronic acid dressing (Healoderm) has been demonstrated in clinical trials to improve wound-healing efficiency and healing rates for diabetic foot ulcers. However, the drug release and degradation behavior of clinically-used hydrogel wound dressings cannot be adjusted according to the wound microenvironment. Due to the intricacy of diabetic wounds, antibiotics and other medications are frequently combined with hydrogel dressings in clinical practice, although these medications are easily hindered by the hostile environment. In this case, scientists have created responsive-hydrogel dressings based on the microenvironment features of diabetic wounds (such as high glucose and low pH) or combined with external stimuli (such as light or magnetic field) to achieve controllable drug release, gel degradation, and microenvironment improvements in order to overcome these clinical issues. These responsive-hydrogel dressings are anticipated to play a significant role in diabetic therapeutic wound dressings. Here, we review recent advances on responsive-hydrogel dressings towards diabetic wound healing, with focus on hydrogel structure design, the principle of responsiveness, and the behavior of degradation. Last but not least, the advantages and limitations of these responsive-hydrogels in clinical applications will also be discussed. We hope that this review will contribute to furthering progress on hydrogels as an improved dressing for diabetic wound healing and practical clinical application.

Multi-functional nanogel with cascade catalytic performance for treatment of diabetic oral mucosa ulcer.

Introduction: Diabetic oral mucosa ulcers face challenges of hypoxia, hyperglycemia and high oxidative stress, which result in delayed healing process. Oxygen is regarded as an important substance in cell proliferation, differentiation and migration, which is beneficial to ulcer recovery. Methods: This study developed a multi-functional GOx-CAT nanogel (GCN) system for the treatment of diabetic oral mucosa ulcers. The catalytic activity, ROS scavenge and oxygen supply ability of GCN was validated. The therapeutic effect of GCN was verified in the diabetic gingival ulcer model. Results: The results showed that the nanoscale GCN was capable of significantly eliminating intracellular ROS, increasing intracellular oxygen concentration and accelerating cell migration of human gingival fibroblasts, which could promote diabetic oral gingival ulcer healing in vivo by alleviating inflammation and promoting angiogenesis. Discussion: This multifunctional GCN with ROS depletion, continuous oxygen supply and good biocompatibility, which might provide a novel therapeutic strategy for effective treatment of diabetic oral mucosa ulcers.

Recent advances in stimuli-responsive polymeric carriers for controllable CRISPR/Cas9 gene editing system delivery.

Non-viral polymeric vectors with good biocompatibility have been recently explored as delivery systems for clustered regularly interspaced short palindromic repeat (CRISPR)-associated (Cas) nucleases. In this review, based on current limitations and critical barriers, we summarize the advantages of stimulus-responsive polymeric delivery vectors (i.e., pH, redox, or enzymes) towards controllable CRISPR/Cas9 genome editing system delivery as well as the advances in using stimulus-responsive CRISPR/Cas9 polymeric carriers towards cancer treatment. Last but not least, the key challenges and promising development strategies of stimulus-responsive polymeric vector designs for CRISPR/Cas9 systems will also be discussed.

Recent Advances in Nanozyme-Based Materials for Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is a type of chronic inflammatory disorder that interferes with the patient's lifestyle and, in extreme situations, can be deadly. Fortunately, with the ever-deepening understanding of the pathological cause of IBD, recent studies using nanozyme-based materials have indicated the potential toward effective IBD treatment. In this review, the recent advancement of nanozymes for the treatment of enteritis is summarized from the perspectives of the structural design of nanozyme-based materials and therapeutic strategies, intending to serve as a reference to produce effective nanozymes for moderating inflammation in the future. Last but not least, the potential and current restrictions for using nanozymes in IBD will also be discussed. In short, this review may provide a guidance for the development of innovative enzyme-mimetic nanomaterials that offer a novel and efficient approach toward the effective treatment of IBD.

The Predictive Value of Heparin-Binding Protein and D-Dimer in Patients with Sepsis.

Objective: To explore the serial measurement of heparin-binding protein and D-dimer in the prediction of 28-day mortality and efficacy evaluation of critically-ill patients with sepsis. Methods: We recruited a total of 51 patients with sepsis in the ICU of our hospital. They were divided into a survival group or a death group according to their prognosis 28 days after treatment. The HBP and D-dimer levels in these patients were determined on the 1st (24h), 3rd, and 5th days. Besides, the sequential organ failure assessment (SOFA) score of these patients was recorded at admission. The patients in both groups were subjected to comparison regarding HBP and D-dimer levels and SOFA scores within 24h of admission. Additionally, a correlation between the levels of HBP and D-dimer and the SOFA score was statistically measured, while the predictive effectiveness of these factors for the prognosis of patients with sepsis was also determined. Moreover, the dynamic changes in HBP and D-dimer during the treatment of both groups were analyzed. Results: The HBP and D-dimer levels and the SOFA scores in the survival group were considerably lower than those in the death group, and the differences were statistically significant (P<0.05). Additionally, the levels of HBP and D-dimer in sepsis patients were positively correlated with the SOFA score (P<0.05). The area under the curve (AUC) of HBP, D-dimer, and their combination in predicting the prognosis of patients with sepsis was 0.824, 0.771, and 0.830, respectively. Besides, the sensitivity and specificity of their combination in predicting the prognosis of patients with sepsis were 68.42% and 92.31%, respectively. The HBP and D-dimer levels presented a downward trend in the survival group during treatment, while they exhibited an upward trend in the death group. Conclusion: HBP and D-dimer realize high predictive effectiveness for the prognosis of patients with sepsis, while the combined use of these two factors achieves superior effectiveness. Thus, they can be applied to the prediction of 28-day mortality and efficacy evaluation of sepsis patients.

Stimuli-Responsive Polymeric Nanovaccines Toward Next-Generation Immunotherapy.

The development of nanovaccines that employ polymeric delivery carriers has garnered substantial interest in therapeutic treatment of cancer and a variety of infectious diseases due to their superior biocompatibility, lower toxicity and reduced immunogenicity. Particularly, stimuli-responsive polymeric nanocarriers show great promise for delivering antigens and adjuvants to targeted immune cells, preventing antigen degradation and clearance, and increasing the uptake of specific antigen-presenting cells, thereby sustaining adaptive immune responses and improving immunotherapy for certain diseases. In this review, the most recent advances in the utilization of stimulus-responsive polymer-based nanovaccines for immunotherapeutic applications are presented. These sophisticated polymeric nanovaccines with diverse functions, aimed at therapeutic administration for disease prevention and immunotherapy, are further classified into several active domains, including pH, temperature, redox, light and ultrasound-sensitive intelligent nanodelivery systems. Finally, the potential strategies for the future design of multifunctional next-generation polymeric nanovaccines by integrating materials science with biological interface are proposed.

Hybrid Polydimethylsiloxane (PDMS) Incorporated Thermogelling System for Effective Liver Cancer Treatment.

For the delivery of anticancer drugs, an injectable in situ hydrogel with thermal responsiveness and prolonged drug release capabilities shows considerable potential. Here, we present a series of thermosensitive in situ hydrogels that serve as drug delivery systems for the treatment of liver cancer. These hydrogels were created by utilizing the polydimethylsiloxane (PDMS) oligomer, polyethylene glycol (PEG) and polypropylene glycol (PPG)'s chemical cross-linking capabilities. Doxorubicin (DOX) was encapsulated in a hydrogel with a hydrophobic core and hydrophilic shell to enhance DOX solubility. Studies into the behavior of in situ produced hydrogels at the microscopic and macroscopic levels revealed that the copolymer solution exhibits a progressive shift from sol to gel as the temperature rises. The hydrogels' chemical composition, thermal properties, rheological characteristics, gelation period, and DOX release behavior were all reported. Subcutaneous injection in mice was used to confirm the injectability. Through the in vitro release of DOX in a PBS solution that mimics the tumor microenvironment, the hydrogel's sustained drug release behavior was confirmed. Additionally, using human hepatocellular hepatoma, the anticancer efficacy of thermogel (DEP-2@DOX) was assessed (HepG2). The carrier polymer material DEP-2 was tested for cytotoxicity using HepG2 cells and its excellent cytocompatibility was confirmed. In conclusion, these thermally responsive injectable hydrogels are prominent potential candidates as drug delivery vehicles for the treatment of hepatocellular carcinoma.

Cholesterol-stabilized membrane-active nanopores with anticancer activities.

Cholesterol-enhanced pore formation is one evolutionary means cholesterol-free bacterial cells utilize to specifically target cholesterol-rich eukaryotic cells, thus escaping the toxicity these membrane-lytic pores might have brought onto themselves. Here, we present a class of artificial cholesterol-dependent nanopores, manifesting nanopore formation sensitivity, up-regulated by cholesterol of up to 50 mol% (relative to the lipid molecules). The high modularity in the amphiphilic molecular backbone enables a facile tuning of pore size and consequently channel activity. Possessing a nano-sized cavity of ~ 1.6 nm in diameter, our most active channel Ch-C1 can transport nanometer-sized molecules as large as 5(6)-carboxyfluorescein and display potent anticancer activity (IC50 = 3.8 µM) toward human hepatocellular carcinomas, with high selectivity index values of 12.5 and >130 against normal human liver and kidney cells, respectively.

Nanoenzyme-chitosan hydrogel complex with cascade catalytic and self-reinforced antibacterial performance for accelerated healing of diabetic wounds.

The significant disability and fatality rate of diabetes chronic wounds necessitates the development of efficient diabetic wound healing techniques. The present oxygen treatments for wound healing is restricted by issues such as poor penetration, inadequate supply, and absorption difficulties as well as tanglesome diabetic wound microenvironment issues such as hyperglycemia, excessive reactive oxygen species (ROS), and hypoxia. Herein, we designed a multifunctional glucose oxidase (GOx) and catalase (CAT) nanoenzyme-chitosan (GCNC) hydrogel complex to improve the microenvironment of diabetic wounds and provide continuous oxygen delivery for efficient wound healing. By simultaneously forming the GOx-CAT nanoenzyme (GCNE) composite, the GCNC hydrogel complex could effectively reduce glucose and ROS (H2O2) concentrations in diabetic wounds through cascade catalytic reactions and achieve continuous oxygen supply, which promoted cell proliferation, migration, and angiogenesis, thereby accelerating diabetic wound healing. In addition, the byproduct gluconic acid produced by the cascade reaction can activate the amino group of chitosan to reinforce the antibacterial performance and prevent microbial infection. This multifunctional GCNC hydrogel complex with continuous oxygen supply, self-reinforcing antibacterial properties, and byproduct-free features provides a general strategy for repairing the extensive tissue damage in diabetes.

Recent advances in mechanical force-responsive drug delivery systems.

Mechanical force responsive drug delivery systems (in terms of mechanical force induced chemical bond breakage or physical structure destabilization) have been recently explored to exhibit a controllable pharmaceutical release behaviour at a molecular level. In comparison with chemical or biological stimulus triggers, mechanical force is not only an external but also an internal stimulus which is closely related to the physiological status of patients. However, although this mechanical force stimulus might be one of the most promising and feasible sources to achieve on-demand pharmaceutical release, current research in this field is still limited. Hence, this tutorial review aims to comprehensively evaluate the recent advances in mechanical force-responsive drug delivery systems based on different types of mechanical force, in terms of direct stimulation by compressive, tensile, and shear force, or indirect/remote stimulation by ultrasound and a magnetic field. Furthermore, the exciting developments and current challenges in this field will also be discussed to provide a blueprint for potential clinical translational research of mechanical force-responsive drug delivery systems.

Research Advances of Injectable Functional Hydrogel Materials in the Treatment of Myocardial Infarction.

Myocardial infarction (MI) has become one of the serious diseases threatening human life and health. However, traditional treatment methods for MI have some limitations, such as irreversible myocardial necrosis and cardiac dysfunction. Fortunately, recent endeavors have shown that hydrogel materials can effectively prevent negative remodeling of the heart and improve the heart function and long-term prognosis of patients with MI due to their good biocompatibility, mechanical properties, and electrical conductivity. Therefore, this review aims to summarize the research progress of injectable hydrogel in the treatment of MI in recent years and to introduce the rational design of injectable hydrogels in myocardial repair. Finally, the potential challenges and perspectives of injectable hydrogel in this field will be discussed, in order to provide theoretical guidance for the development of new and effective treatment strategies for MI.

Oxygen self-supplied enzyme nanogels for tumor targeting with amplified synergistic starvation and photodynamic therapy.

Tumor tissues need vast supply of nutrients and energy to sustain the rapid proliferation of cancer cells. Cutting off the glucose supply represents a promising cancer therapy approach. Herein, a tumor tissue-targeted enzyme nanogel (rGCP nanogel) with self-supply oxygen capability was developed. The enzyme nanogel synergistically enhanced starvation therapy and photodynamic therapy (PDT) to mitigate the rapid proliferation of cancer cells. The rGCP nanogel was fabricated by copolymerizing two monomers, porphyrin and cancer cells-targeted, Arg-Gly-Asp (RGD), onto the glucose oxidase (GOX) and catalase (CAT) surfaces. The cascade reaction within the rGCP nanogel could efficiently consume intracellular glucose catalyzed by GOX. Concurrently, CAT safely decomposed the produced H2O2 with systemic toxicity to promote oxygen generation and achieved low toxicity starvation therapy. The produced oxygen subsequently facilitated the glucose oxidation reaction and significantly enhanced the generation of cytotoxic singlet oxygen (1O2) in the presence of 660 nm light irradiation. Combining starvation therapy and PDT, the designed enzyme nanogel system presented an amplified synergic cancer therapy effect. This approach potentially paved a new way to fabricate a combinatorial therapy approach by employing cascaded catalytic nanomedicines with good tumor selectivity and efficient anti-cancer effect. STATEMENT OF SIGNIFICANCE: The performance of starvation and photodynamic therapy (PDT) is usually suppressed by intrinsic tumorous hypoxia. Herein, an oxygen self-supplied and tumor tissue-targeted enzyme nanogel was created by copolymerization of two monomers, porphyrin and cancer cell-targeted Arg-Gly-Asp (RGD), onto the surface of glucose oxidase (GOX) and catalase (CAT), which synergistically enhanced starvation therapy and PDT. Moreover, the enzyme nanogels possessed high stability and could be synthesized straightforwardly. This anti-cancer system provides an approach for constructing a combinatorial therapy approach by employing cascaded catalytic nanomedicine with good tumor selectivity and therapeutic efficacy.

Fabricating Dual-Functional Plasmonic-Magnetic Au@MgFe2O4 Nanohybrids for Photothermal Therapy and Magnetic Resonance Imaging.

Bifunctional nanohybrids possessing both plasmonic and magnetic functionalities are of great interest for biomedical applications owing to their capability for simultaneous therapy and diagnostics. Herein, we fabricate a core-shell structured plasmonic-magnetic nanocomposite system that can serve as a dual-functional agent due to its combined photothermal therapeutic and magnetic resonance imaging (MRI) functions. The photothermal activity of the hybrid is attributed to its plasmonic Au core, which is capable of absorbing near-infrared (NIR) light and converting it into heat. Meanwhile, the magnetic MgFe2O4 shell exerts its ability to act as a MRI contrast agent. Our in vivo studies using tumor-bearing mice demonstrated the nanohybrids' excellent photothermal and MRI properties. As a photothermal therapeutic agent, the nanohybrids were able to dramatically shrink solid tumors in mice through NIR-induced hyperthermia. As T 2-weighted MRI contrast agents, the nanohybrids were found capable of substantially reducing the MRI signal intensity of the tumor region at 10 min postinjection. With their dual plasmonic-magnetic functionality, these Au@MgFe2O4 nanohybrids hold great promise not only in the biomedical field but also in the areas of catalysis and optical sensing.

Dual Tumor Microenvironment Remodeling by Glucose-Contained Radical Copolymer for MRI-Guided Photoimmunotherapy.

Aberrant glucose metabolism and immune evasion are recognized as two hallmarks of cancer, which contribute to poor treatment efficiency and tumor progression. Herein, a novel material system consisting of a glucose and TEMPO (2,2,6,6-tetramethylpiperidin-1-yl)oxyl) at the distal ends of PEO-b-PLLA block copolymer (glucose-PEO-b-PLLA-TEMPO), is designed to encapsulate clinical therapeutics CUDC101 and photosensitizer IR780. The specific core-shell rod structure formed by the designed copolymer renders TEMPO radicals excellent stability against reduction-induced magnetic resonance imaging (MRI) silence. Tumor-targeting moiety endowed by glucose provides the radical copolymer outstanding multimodal imaging capabilities, including MRI, photoacoustic imaging, and fluorescence imaging. Efficient delivery of CUDC101 and IR780 is achieved to synergize the antitumor immune activation through IR780-mediated photodynamic therapy (PDT) and CUDC101-triggered CD47 inhibition, showing M1 phenotype polarization of tumor-associated macrophages (TAMs). More intriguingly, this study demonstrates PDT-stimulated p53 can also re-educate TAMs, providing a combined strategy of using dual tumor microenvironment remodeling to achieve the synergistic effect in the transition from cold immunosuppressive to hot immunoresponsive tumor microenvironment.

Effectiveness of an ocular adhesive polyhedral oligomeric silsesquioxane hybrid thermo-responsive FK506 hydrogel in a murine model of dry eye.

Dry eye is a common ocular disease that results in discomfort and impaired vision, impacting an individual's quality of life. A great number of drugs administered in eye drops to treat dry eye are poorly soluble in water and are rapidly eliminated from the ocular surface, which limits their therapeutic effects. Therefore, it is imperative to design a novel drug delivery system that not only improves the water solubility of the drug but also prolongs its retention time on the ocular surface. Herein, we develop a copolymer from mono-functional POSS, PEG, and PPG (MPOSS-PEG-PPG, MPEP) that exhibits temperature-sensitive sol-gel transition behavior. This thermo-responsive hydrogel improves the water solubility of FK506 and simultaneously provides a mucoadhesive, long-acting ocular delivery system. In addition, the FK506-loaded POSS hydrogel possesses good biocompatibility and significantly improves adhesion to the ocular surface. In comparison with other FK506 formulations and the PEG-PPG-FK506 (F127-FK506) hydrogel, this novel MPOSS-PEG-PPG-FK506 (MPEP-FK506) hydrogel is a more effective treatment of dry eye in the murine dry eye model. Therefore, delivery of FK506 in this POSS hydrogel has the potential to prolong drug retention time on the ocular surface, which will improve its therapeutic efficacy in the management of dry eye.