A Hybrid Supramolecular Polymeric Nanomedicine for Cascade-Amplified Synergetic Cancer Therapy.

Supramolecular nanomedicines have shown great merits in cancer therapy, but their clinical translation is hampered by monotonous therapeutic modality and unsatisfactory antitumor performance. Herein, a hybrid supramolecular polymeric nanomedicine (SNPs) is developed based on ß-cyclodextrin/camptothecin (CPT) host-guest molecular recognition and iron-carboxylate coordination. Iron ions stabilizing SNPs catalyze the conversion of intracellular hydrogen peroxide into highly toxic hydroxyl radical through a Fenton reaction, which further cleaves the thioketal linker of the supramolecular monomer to release potent CPT, thus amplifying the therapeutic efficacy by combining chemodynamic therapy and chemotherapy. The combination therapy stimulates antitumor immunity and promotes intratumoral infiltration of cytotoxic T lymphocytes by triggering immunogenic cell death. In synergy with PD-L1 checkpoint blockade, SNPs enables enhanced immune therapy and a long-term tumor remission.

Cell-derived extracellular vesicles and membranes for tissue repair.

Humans have a limited postinjury regenerative ability. Therefore, cell-derived biomaterials have long been utilized for tissue repair. Cells with multipotent differentiation potential, such as stem cells, have been administered to patients for the treatment of various diseases. Researchers expected that these cells would mediate tissue repair and regeneration through their multipotency. However, increasing evidence has suggested that in most stem cell therapies, the paracrine effect but not cell differentiation or regeneration is the major driving force of tissue repair. Additionally, ethical and safety problems have limited the application of stem cell therapies. Therefore, nonliving cell-derived techniques such as extracellular vesicle (EV) therapy and cell membrane-based therapy to fulfil the unmet demand for tissue repair are important. Nonliving cell-derived biomaterials are safer and more controllable, and their efficacy is easier to enhance through bioengineering approaches. Here, we described the development and evolution from cell therapy to EV therapy and cell membrane-based therapy for tissue repair. Furthermore, the latest advances in nonliving cell-derived therapies empowered by advanced engineering techniques are emphatically reviewed, and their potential and challenges in the future are discussed.

Impact of Antifouling PEG Layer on the Performance of Functional Peptides in Regulating Cell Behaviors.

Cell adhesive and other functional peptides (such as RGD, KRSR, YIGSR, VAPG, and BMP-2 peptides) are extensively studied and utilized in tissue engineering scaffolds and biomedical devices to modulate cell functions. Though PEG is frequently used as the antifouling layer, it is unclear how it affects the performance of functional peptides. By analyzing the impact of PEG at short (OEG4), medium (OEG8), and long chain length (PEG2K), we reveal that PEG chain length is critical and a medium-length PEG enables functional peptides to display their optimal and genuine functions in cell adhesion, migration, and differentiation by providing excellent antifouling to minimize background noise of unwanted cell adhesion and high enough surface density of functional peptides. Our result provides new avenues for maximizing the genuine functions of peptides. This study also provides a solution to prevent the heterogeneous and even divergent results caused by inappropriate choice of antifouling PEG and provides a general guidance in identifying new functional peptides.

Antitumor Activity of a Unique Polymer That Incorporates a Fluorescent Self-Assembled Metallacycle.

Despite the well-known anticancer activity of mono- and multinuclear platinum complexes, studies of the antitumor performances of platinum-based supramolecular coordination complexes are rare. Herein, we report on the synthesis of a four-armed amphiphilic copolymer, Pt-PAZMB-b-POEGMA, containing a metallacycle M, in which the tetraphenylethene derivative acts as an aggregation-induced emissive fluorescent probe for live cell imaging and the 3,6-bis[trans-Pt(PEt3)2]phenanthrene (PhenPt) is an anticancer drug. This copolymer was further self-assembled into nanoparticles of different sizes and vesicles depending upon the experimental conditions. The impacts of the morphology and size of the assemblies on their endocytic pathways, uptake rates, internalization amounts, and cytotoxicities were investigated. The self-assemblies were further employed to encapsulate doxorubicin (DOX) to achieve a synergistic anticancer effect. Controlled drug release was also realized via amphiphilicity changes and was driven by a glutathione-induced cascade elimination reaction. The DOX-loaded nanoparticles of around 50 nm in size exhibited an excellent antitumor performance as well as a low systemic toxicity, due to an enhanced permeability and retention effect.

Complementary density gradient of Poly(hydroxyethyl methacrylate) and YIGSR selectively guides migration of endotheliocytes.

Selective enhancement of directional migration of endotheliocytes (ECs) over vascular smooth muscle cells (SMCs) plays a significant role for the fast endothelialization of blood-contacting implants, in particular for the antirestenosis of vascular stents. Herein, a complementary density gradient of poly(2-hydroxyethyl methacrylate) (PHEMA) brushes and YIGSR peptide, a sequence specifically improving the mobility of ECs, was fabricated using a dynamically controlled reaction process. The gradients were visualized by fluorescent labeling and further quantified by X-ray photoelectron spectrometry (XPS) and quartz crystal microbalance with dissipation (QCM-d). The ECs exhibited preferential orientation and enhanced directional migration behavior on the gradient surface toward the region of lower PHEMA density and higher YIGSR density. The migration rate of the ECs was significantly enhanced to 5-fold, whereas the mobility of SMCs was not significantly influenced, leading to faster migration of ECs than SMCs. Therefore, the success of the complementary gradient relies on the appropriate interplay between the PHEMA brushes and the cell-specific ligands, enabling the selective guidance of EC migration.

ATP-Responsive Manganese-Based Bacterial Materials Synergistically Activate the cGAS-STING Pathway for Tumor Immunotherapy.

Stimulating the cyclic guanosine monophophate(GMP)-adenosine monophosphate (AMP) synthase (cGAS)-stimulator of interferon genes (STING) pathway is a crucial strategy by which bacteria activate the tumor immune system. However, the limited stimulation capability poses significant challenges in advancing bacterial immunotherapy. Here, an adenosine 5'-triphosphate (ATP)-responsive manganese (Mn)-based bacterial material (E. coli@PDMC-PEG (polyethylene glycol)) is engineered successfully, which exhibits an exceptional ability to synergistically activate the cGAS-STING pathway. In the tumor microenvironment, which is characterized by elevated ATP levels, this biohybrid material degrades, resulting in the release of divalent manganese ions (Mn2+) and subsequent bacteria exposure. This combination synergistically activates the cGAS-STING pathway, as Mn2+ enhances the sensitivity of cGAS to the extracellular DNA (eDNA) secreted by the bacteria. The results of the in vivo experiments demonstrate that the biohybrid materials E. coli@PDMC-PEG and VNP20009@PDMC-PEG effectively inhibit the growth of subcutaneous melanoma in mice and in situ liver cancer in rabbits. Valuable insights for the development of bacteria-based tumor immunotherapy are provided here.

Inflammation-Responsive Cell Membrane-Camouflaged Nanoparticles against Liver Fibrosis via Regulating Endoplasmic Reticulum Stress and Oxidative Stress.

Liver fibrosis represents a reversible stage of various chronic liver diseases that progresses to cirrhosis. This condition is characterized by an imbalance between tissue damage and repair, and the production of fibers in the liver exceeds their degradation. Oxidative stress (OS) resulting from tissue injury and endoplasmic reticulum stress (ERS) triggered by the overproduction of proteins are pivotal factors in liver fibrosis. Melatonin demonstrates the capability to neutralize free radicals, shielding cells from oxidative harm. It is also a specific inhibitor of the ERS receptor transcription activating factor 6 (ATF6), indicating its great potential in ameliorating liver fibrosis. However, its limited water solubility and oral bioavailability of under 15% present hurdles in achieving therapeutic blood concentrations for treating liver fibrosis. The PLGA@Melatonin is constructed by loading melatonin with poly (lactic-co-glycolic acid) (PLGA). Platelet membranes (PM) and activated hepatic stellate cell membranes (HSCM) with high expression of the platelet-derived growth factor receptor (PDGFR) are extracted to successfully construct PM@PLGA@Melatonin and HSCM@PLGA@Melatonin, which are subsequently utilized to treat mice with liver fibrosis. The results illustrated the remarkable therapeutic effects of the two nanoparticles on liver fibrosis, along with their excellent targeting and biosafety properties.

Supramolecular Lipid Nanoparticles Based on Host-Guest Recognition: A New Generation Delivery System of mRNA Vaccines For Cancer Immunotherapy.

Dendritic cell (DC) maturation is a crucial process for antigen presentation and the initiation of T cell-mediated immune responses. Toll-like receptors play pivotal roles in stimulating DC maturation and promoting antigen presentation. Here, a novel message RNA (mRNA) cancer vaccine is reported that boosts antitumor efficacy by codelivering an mRNA encoding tumor antigen and a TLR7/8 agonist (R848) to DC using supramolecular lipid nanoparticles (SMLNP) as a delivery platform, in which a new ionizable lipid (N2-3L) remarkably enhances the translation efficiency of mRNA and a ß-cyclodextrin (ß-CD)-modified ionizable lipid (Lip-CD) encapsulates R848. The incorporation of R848 adjuvant into the mRNA vaccine through noncovalent host-guest complexation significantly promotes DC maturation and antigen presentation after vaccination, thus resulting in superior antitumor efficacy in vivo. Moreover, the antitumor efficacy is further boosted synergized with immune checkpoint blockade by potentiating the anticancer capability of cytotoxic T lymphocytes infiltrated in tumor sites. This work indicates that SMLNP shows brilliant potential as next-generation delivery system in the development of mRNA vaccines with high efficacy.

Celecoxib Augments Paclitaxel-Induced Immunogenic Cell Death in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a highly aggressive malignancy that lacks effective targeted therapies. Inducing immunogenic cell death (ICD) in tumor cells represents a promising strategy to enhance therapeutic efficacy by promoting antitumor immunity. Paclitaxel (PTX), a commonly used chemotherapy drug for TNBC, can induce ICD; however, the resulting immunogenicity is limited. Thus, there is an urgent need to explore strategies that improve the effectiveness of ICD in TNBC by incorporating immunoregulatory agents. This study investigated the potential of celecoxib (CXB) to enhance PTX-induced ICD by blocking the biosynthesis of PGE2 in the tumor cells. We observed that the combination of CXB and PTX promoted the maturation of dendritic cells and primed a T cell-dependent immune response, leading to enhanced tumor rejection in a vaccination assay. To further optimize drug delivery in vivo, we developed cRGD-modified liposomes for the targeted codelivery of CXB and PTX. This delivery system significantly improved drug accumulation and triggered robust antitumor immunity in an orthotopic mouse model of TNBC. Moreover, it served as an in situ vaccine to inhibit tumor recurrence and lung metastasis. Overall, our findings provide in-depth insights into the therapeutic mechanism underlying the combination of CXB and PTX, highlighting their potential as effective immune-based therapies for TNBC.

Dual-Responsive Supramolecular Polymeric Nanomedicine for Self-Cascade Amplified Cancer Immunotherapy.

Insufficient tumor immunogenicity and immune escape from tumors remain common problems in all tumor immunotherapies. Recent studies have shown that pyroptosis, a form of programmed cell death that is accompanied by immune checkpoint inhibitors, can induce effective immunogenic cell death and long-term immune activation. Therapeutic strategies to jointly induce pyroptosis and reverse immunosuppressive tumor microenvironments are promising for cancer immunotherapy. In this regard, a dual-responsive supramolecular polymeric nanomedicine (NCSNPs) to self-cascade amplify the benefits of cancer immunotherapy is designed. The NCSNPs are formulated by ß-cyclodextrin coupling nitric oxide (NO) donor, a pyroptosis activator, and NLG919, an indoleamine 2,3-dioxygenase (IDO) inhibitor, and self-assembled through host-guest molecular recognition and hydrophobic interaction to obtain nanoparticles. NCSNPs possess excellent tumor accumulation and bioavailability attributed to ingenious supramolecular engineering. The study not only confirms the occurrence of NO-triggered pyroptosis in tumors for the first time but also reverses the immunosuppressive microenvironment in tumor sites via an IDO inhibitor by enhancing the infiltration of cytotoxic T lymphocytes, to achieve remarkable inhibition of tumor proliferation. Thus, this study provides a novel strategy for cancer immunotherapy.

Hybrid Membrane-Coated Nanoparticles for Precise Targeting and Synergistic Therapy in Alzheimer's Disease.

The blood brain barrier (BBB) limits the application of most therapeutic drugs for neurological diseases (NDs). Hybrid cell membrane-coated nanoparticles derived from different cell types can mimic the surface properties and functionalities of the source cells, further enhancing their targeting precision and therapeutic efficacy. Neuroinflammation has been increasingly recognized as a critical factor in the pathogenesis of various NDs, especially Alzheimer's disease (AD). In this study, a novel cell membrane coating is designed by hybridizing the membrane from platelets and chemokine (C-C motif) receptor 2 (CCR2) cells are overexpressed to cross the BBB and target neuroinflammatory lesions. Past unsuccessful endeavors in AD drug development underscore the challenge of achieving favorable outcomes when utilizing single-mechanism drugs.Two drugs with different mechanisms of actions into liposomes are successfully loaded to realize multitargeting treatment. In a transgenic mouse model for familial AD (5xFAD), the administration of these drug-loaded hybrid cell membrane liposomes results in a significant reduction in amyloid plaque deposition, neuroinflammation, and cognitive impairments. Collectively, the hybrid cell membrane-coated nanomaterials offer new opportunities for precise drug delivery and disease-specific targeting, which represent a versatile platform for targeted therapy in AD.

Directional migration of vascular smooth muscle cells guided by a molecule weight gradient of poly(2-hydroxyethyl methacrylate) brushes.

Directional migration of cells mediated by gradient cues in vitro can mimic the corresponding biological events in vivo and thereby provides a way to disclose the cascade responses in tissue regeneration processes and to develop novel criteria for design of tissue-inductive biomaterials. In this work, a molecular weight gradient of poly(2-hydroxyethyl methacrylate) (PHEMA) brushes with a thickness ranging from 3 to 30 nm and slopes of 0.8-3.2 nm/mm were fabricated by using surface-initiated atom transfer radical polymerization (ATRP) and a dynamically controlled reaction process. The PHEMA gradients were characterized by X-ray photoelectron spectrometry (XPS) and ellipsometry. The adhesion number, spreading area, adhesion force, and expression of focal adhesion and actin fibers of vascular smooth muscle cells (VSMCs) decreased along with the increase of the PHEMA brushes length. The VSMCs exhibited preferential orientation and enhanced directional migration toward the direction of reduced PHEMA thickness, whose extent was dependent on the gradient slope and polymer thickness. Most of the cells were oriented, and 87% of the cells moved directionally at the optimal conditions.

Control over the gradient differentiation of rat BMSCs on a PCL membrane with surface-immobilized alendronate gradient.

Gradient biomaterials can offer progressively changing signals to specific tissue interface, and thereby modulate the conjunction between different tissues. A linear density gradient of alendronate (Aln), a molecule that is capable of promoting osteogenic differentiation of bone mesenchymal stem cells (BMSCs), was created on an aminolyzed poly(ε-caprolactone) (PCL) membrane. X-ray photoelectron spectroscopy and quartz crystal microbalance with dissipation revealed the linear increase of the Aln amount as a function of the position on the PCL membrane. By contrast, the surface wettability and energy were kept unchanged. The surface-grafted Aln showed a stronger ability to induce the osteogenic differentiation of rat BMSCs than its counterpart in culture medium of the same amount, and the osteo-inductive culture medium. On the Aln-grafted gradient surface, the BMSCs showed gradient osteogenic differentiation as a function of membrane position in terms of cell morphology, alkaline phosphatase activity, calcium deposition, and the expression of osteogenesis marker proteins including collagen type I (COL I), Runt-related transcription factor 2 (Runx2), and osteocalcin (OCN).

Influence of surface coating of PLGA particles on the internalization and functions of human endothelial cells.

This study is focused on the uptake of PLGA particles with different coatings and its influences on the functions and toxicity of human endothelial cells. The PLGA particles coated with polyethyleneimine (PEI) or bovine serum albumin (BSA) were prepared via a one-step emulsion method, which had a similar diameter of ∼420 nm in water and ∼170 nm in a dry state but oppositely charged surfaces. Both types of the particles were readily internalized into cells within a short time regardless of their surface chemistry. Uptake of the positively charged particles caused apparently a decrease in cell viability, but did not significantly influence mitochondrial membrane potential and activity of caspase-3. The cell adhesion and migration were significantly affected, especially after uptake of the PLGA-PEI particles. The secretion levels of von Willebrand factor (vWF) and 6-k-PGF(1α) were not significantly influenced regardless of the surface coating.

Cells as factories for humanized encapsulation.

Biocompatibility is of paramount importance for drug delivery, tumor labeling, and in vivo application of nanoscale bioprobes. Until now, biocompatible surface processing has typically relied on PEGylation and other surface coatings, which, however, cannot minimize clearance by macrophages or the renal system but may also increase the risk of chemical side effects. Cell membranes provide a generic and far more natural approach to the challenges of encapsulation and delivery in vivo. Here we harness for the first time living cells as "factories" to manufacture cell membrane capsules for encapsulation and delivery of drugs, nanoparticles, and other biolabels. Furthermore, we demonstrate that the built-in protein channels of the new capsules can be utilized for controlled release of encapsulated reagents.

Mesoporous polydopamine nanoparticles for sustained release of rapamycin and reactive oxygen species scavenging to synergistically accelerate neurogenesis after spinal cord injury.

Spinal cord injury (SCI) is an intractable condition with complex pathological processes and poor prognosis. Reactive oxygen species (ROS) generation induced by the mammalian target of the rapamycin (mTOR) protein is one of the causes of secondary inflammation of SCI. Rapamycin (Rapa) is a pharmacological inhibitor of mTOR, which can inhibit ROS overproduction mediated by abnormal activation of the mTOR protein. Polydopamine, as a nanocarrier with excellent biological safety, has been reported to possess satisfactory ROS scavenging ability. Therefore, we designed a mesoporous polydopamine nanoparticle loaded with Rapa (mPDA@Rapa) for combination therapy, which simultaneously inhibited abnormally activated mTOR-mediated ROS production and eliminated already generated ROS. The synthesized mPDA nanoparticles could realize the effective encapsulation and sustained release of Rapa due to their mesoporous cavities and a hydrophobic benzene ring structure. In vitro experiments proved that mPDA@Rapa nanoparticles had a good ROS scavenging ability towards hydrogen peroxide and hydroxyl radicals. Furthermore, mPDA@Rapa also showed a good therapeutic effect in SCI model rats, which was evidenced by a smaller injury cavity, more coordinated hind limb movements, and a higher degree of neurogenesis and tissue regeneration. Our work provides a combined strategy to inhibit ROS overproduction and eliminate excess ROS, with potential applications not only in SCI, but also in other ROS-induced inflammations.

Nanodefensin-encased hydrogel with dual bactericidal and pro-regenerative functions for advanced wound therapy.

Background: Host defense peptides (HDPs) have emerged as a novel therapeutic paradigm for wound management; however, their clinical applications remain a challenge owing to their poor pharmacological properties and lack of suitable pharmaceutical formulations. Nanodefensin (ND), a nanoengineered human α-defensin 5 (HD5), has shown improved pharmacological properties relative to the parent compound. In this study, we engineered a nanodefensin-encased hydrogel (NDEFgel), investigated the effects of NDEFgel on wound healing, and elucidated underlying mechanisms. Method: ND was chemically synthesized and tested functions by in vitro antimicrobial and scratch assays and western blotting. Different NDEFgels were evaluated by in vitro characterizations including degradation, drug release and antimicrobial activity. In full-thickness excisional murine models, the optimal NDEFgel was directly applied onto wound sites, and the efficacy was assessed. Moreover, the underlying mechanisms of pro-regenerative effect developed by NDEFgel were also explored. Results: Apart from bactericidal effects, ND modulated fibroblast behaviors by promoting migration and differentiation. Among the tested hydrogels, the Pluronic F127 (Plu) hydrogel represented the most desirable carrier for ND delivery owing to its favorable controlled release and compatibility with ND. Local treatment of NDEFgel on the wound bed resulted in accelerated wound regeneration and attenuated bacterial burden. We further demonstrated that NDEFgel therapy significantly upregulated genes related to collagen deposition and fibroblasts, and increased the expression of myofibroblasts and Rac1. We therefore found that Rac1 is a critical factor in the ND-induced modulation of fibroblast behaviors in vitro through a Rac1-dependent cytoskeletal rearrangement. Conclusion: Our results indicate that NDEFgel may be a promising dual-action therapeutic option for advanced wound management in the future.

Finely tuned Prussian blue-based nanoparticles and their application in disease treatment.

The Prussian blue (PB) based nanostructure is a mixed-valence coordination network with excellent biosafety, remarkable photothermal effect and multiple enzyme-mimicking behaviours. Compared with other nanomaterials, PB-based nanoparticles (NPs) exhibit several unparalleled advantages in biomedical applications. This review begins with the chemical composition and physicochemical properties of PB-based NPs. The tuning strategies of PB-based NPs and their biomedical properties are systemically demonstrated. Afterwards, the biomedical applications of PB-based NPs are comprehensively recounted, mainly focusing on treatment of tumors, bacterial infection and inflammatory diseases. Finally, the challenges and future prospects of PB-based NPs and their application in disease treatment are discussed.

Inflammation-targeting polymeric nanoparticles deliver sparfloxacin and tacrolimus for combating acute lung sepsis.

Sepsis is a complex disorder with very high morbidity and mortality; it can occur when an immune disorder triggers an invasion of pathogens in the host. Although many potential anti-infective and immunosuppressive treatments have been reported, we still do not have effective means of treating sepsis in clinic. The aim of this study is to develop a nanomaterial system that targets the site of inflammation and carries a combination of multiple drugs to better treat sepsis and alleviate its symptoms. We selected poly(lactide-co-glycolide acid) (PLGA) with good biocompatibility and degradability to prepare the nanoparticles (NPs) loaded with broad-spectrum antibiotic Sparfloxacin (SFX) and anti-inflammatory immunosuppressant Tacrolimus (TAC) by an emulsion-solvent evaporation method. The targeting ability of the NPs toward inflammatory sites is endowed by grafting of the γ3 peptide (NNQKIVNLKEKVAQLEA) that can specifically bind to the intercellular adhesion molecule-1 (ICAM-1), which is highly expressed on the surface of inflammatory endothelial cells. The drug loaded γ3-PLGA NPs have excellent cytocompatibility, low hemolysis ratio, and systemic toxicity. The drug loaded γ3-PLGA NPs also have excellent antibacterial property to both Gram-positive and Gram-negative bacteria and can effectively reduce the inflammation and immune response in acute lung infection mice. This study provides a simple and robust nanoplatform to treat lung infection induced sepsis, which may pave a way to design multifunctional nanomedicine for clinical translation.

Tumor-Targeting Polycaprolactone Nanoparticles with Codelivery of Paclitaxel and IR780 for Combinational Therapy of Drug-Resistant Ovarian Cancer.

Synergetic treatments that combine chemotherapy with photothermal/photodynamic therapy have been developed as promising new strategies for cancer therapy, especially for drug-resistant cancers. To achieve optimized synergetic outcomes for cancer therapy, it is highly desirable to selectively and simultaneously deliver both chemotherapeutics and near-infrared photosensitizers to the cancer tissues and cells, enhancing local accumulation. Here we report the preparation of poly-ε-caprolactone nanoparticles (PCL NPs) using bovine albumin as a stabilizer; the nanoparticles are loaded with IR780 and paclitaxel (PTX) for combinational phototherapy and chemotherapy. Moreover, in order to enable active targeting toward ovarian cancer, a specific peptide recognizing luteinizing hormone-releasing hormone receptors (LHRH) on ovarian cancer cells was covalently grafted onto the surface of the as-prepared NPs. As a result, LHRH peptide modified PCL (PCL-LHRH) NPs demonstrated increased internalization in ovarian tumor cells in vitro and selective targeting in tumor xenografts in vivo. PTX and IR780 can be efficiently encapsulated into PCL-LHRH NPs by an oil-in-water emulsion and solvent evaporation method. The systematic administration of ovarian tumor targeting PCL-LHRH/IR780-PTX can efficiently hinder the growth of drug-resistant xenografts in vivo with the assistance of an 808 nm near-infrared laser. These findings indicate that peptide mediated tumor targeting multifunctional nanomaterials may have remarkable profits in controlled drug delivery and synergistic therapy on drug-resistant cancer.