Supramolecular Macrophage-Liposome Marriage for Cell-Hitchhiking Delivery and Immunotherapy of Acute Pneumonia and Melanoma

As many diseases are related to inflammation, the inflammatory tropism of immune cells may bring cell-hitchhikers directly to the disease tissues in a highly targeted manner. The current cell-hitchhiking strategies rely on either cellular internalization or covalent surface conjugation, which often affects the physiological function of transporting cells. Herein, a cell-friendly, host-guest chemistry mediated macrophage-liposome conjugate (M-L) is developed for extremely stable cell-hitchhiking drug delivery. M-L is prepared via simple supramolecular “hand-holding” and marriage between cucurbit[7]uril (CB[7]) and adamantane, respectively anchored on the surface of the macrophage and liposome, which demonstrates targeted accumulation in the inflamed lung and effective therapy of acute pneumonia in mice when loaded with quercetin. Upon loading toxic chemotherapeutic agents (such as doxorubicin and oxaliplatin), M-L carries the payloads to the inflammatory cancer tissue and significantly enhances the chemoimmunotherapy of melanoma in mice. Fundamentally, this CB[7]-based supramolecular M-L conjugation strategy shows negligible effects on the migratory and invasive behaviors of macrophages. In vivo pathological analysis of the inflammatory tissues in mice after treatment with M-L further suggests that macrophage and liposomes are delivered together hand in hand. This CB[7]-based, supramolecular cell-conjugation strategy potentially addresses the key challenges faced by the current cell-based delivery systems.     

Macrophage Hitchhiking Nanoparticles for the Treatment of Myocardial Infarction: An In Vitro and In Vivo Study

Myocardial infarction (MI) is the leading cause of death worldwide. However, current therapies are unable to restore the function of the injured myocardium. Advanced approaches, such as stimulation of cardiomyocyte (CM) proliferation are promising, but suffer from poor pharmacokinetics and possible systemic adverse effects. Nanomedicines can be a solution to the above-mentioned drawbacks. However, targeting the cardiac tissue still represents a challenge. Herein, a MI-selective precision nanosystem is developed, that relies on the heart targeting properties of atrial natriuretic peptide (ANP) and lin-TT1 peptide-mediated hitchhiking on M2-like macrophages. The system based on pH-responsive putrescine-modified acetalated dextran (Putre-AcDEX) nanoparticles, shows biocompatibility with cultured cardiac cells, and ANP receptor-dependent interaction with CMs. Moreover, treatment with nanoparticles (NPs) loaded with two pleiotropic cellular self-renewal promoting compounds, CHIR99021 and SB203580, induces a 4-fold increase in bromodeoxyuridine (BrdU) incorporation in primary cardiomyocytes compared to control. In vivo studies confirm that M2-like macrophages targeting by lin-TT1 peptide enhances the heart targeting of ANP. In addition, NP administration does not alter the immunological profile of blood and spleen, showing the short-term safety of the developed system in vivo. Overall, the study results in the development of a peptide-guided precision nanosystem for delivery of therapeutic compounds to the infarcted heart.     

Modulation of Macrophages by In Situ Ligand Bridging

Extracellular matrix (ECM) proteins containing cell-attachable Arg-Gly-Asp (RGD) sequences exhibit variable bridging and non-bridging in fibronectin-collagen and laminin-collagen complexes that can regulate inflammation, tissue repair, and wound healing. In this study, linking molecule-mediated conjugation of 1D magnetic nanocylinders (MNCs) to material surfaces pre-decorated with gold nanospheres (GNSs) is performed, thereby yielding RGD-coated MNCs (RGD-MNCs) over RGD-coated GNSs (RGD-GNSs) in a non-bridging state. The RGD-MNCs are drawn closer to the RGD-GNSs via magnetic field-mediated compression of the linking molecules to establish the bridging between them. Relative proportion of the RGD-MNCs to the RGD-GNSs is optimized to yield effective remote stimulation of integrin binding to variably bridged RGDs similar to that of invariably bridged RGDs used as a control group. Remote manipulation of the RGD bridging facilitates the attachment structure assembly of macrophages that leads to pro-healing/anti-inflammatory phenotype acquisition. In contrast, the non-bridged RGDs inhibited macrophage attachment that acquired pro-inflammatory phenotypes. The use of various nanomaterials in constructing heterogeneous RGD-coated materials can further offer various modes in remote switching of RGD bridging and non-bridging to understand dynamic integrin-mediated modulation of macrophages that regulate immunomodulatory responses, such as foreign body responses, tissue repair, and wound healing.     

Engineering Bioactive M2 Macrophage-Polarized Anti-Inflammatory,Antioxidant, and Antibacterial Scaffolds for Rapid Angiogenesis and Diabetic Wound Repair

Diabetic wound healing still faces great challenges due to the excessive inflammation, easy infection, and impaired angiogenesis in wound beds. The immunoregulation of macrophages polarization toward M2 phenotype that facilitates the transition from inflammation to proliferation phase has been proved to be an effective way to improve diabetic wound healing. Herein, an M2 phenotype-enabled anti-inflammatory, antioxidant, and antibacterial conductive hydrogel scaffolds (GDFE) for producing rapid angiogenesis and diabetic wound repair are reported. The GDFE scaffolds are fabricated facilely through the dynamic crosslinking between polypeptide and polydopamine and graphene oxide. The GDFE scaffolds possess thermosensitivity, self-healing behavior, injectability, broad-spectrum antibacterial activity, antioxidant and anti-inflammatory ability, and electronic conductivity. GDFE effectively activates the polarization of macrophages toward M2 phenotype and significantly promotes the proliferation of dermal fibroblasts, the migration, and in vitro angiogenesis of endothelial cells through paracrine mechanisms. The in vivo results from a full-thickness diabetic wound model demonstrate that GDFE can rapidly promote the diabetic wound repair and skin regeneration, through fast anti-inflammation and angiogenesis and M2 macrophage polarization. This study provides highly efficient strategy for treating diabetic wound repair through designing the M2 polarization-enabled anti-inflammatory, antioxidant, and antibacterial bioactive materials.     

Glycyrrhetinic Acid Liposomes Encapsulated Microcapsules from Microfluidic Electrospray for Inflammatory Wound Healing

In diabetic wound healing, M1 macrophage accumulation and elevated inflammation are prevalent issues. Intelligent delivery systems that can sustainably release antioxidizing and anti-inflammatory ingredients are expected for effective wound healing. Herein, a novel glycyrrhetinic acid (GA) liposomes encapsulated microcapsules delivery system that has desired features for inflammatory wound repair is presented. As the bacteria could break down the alginate shells, the GA liposomes could be controllably released from the microcapsules, which promotes M2 macrophage polarization and regulate their responses in the inflammatory wound microenvironment. Based on these, it is demonstrated that the GA liposomes encapsulated microcapsules delivery system exhibits an anti-inflammatory and immunomodulatory effect for diabetic wound healing in a full-thickness defect model in diabetic rats. These results indicate that the immunomodulatory capabilities of the microcapsules can be unitized for efficient wound repair, and such a delivery system is valuable for clinical wound healing applications.     

Switching On and Off Macrophages by a “Bridge-Burning” Coating Improves Bone-Implant Integration under Osteoporosis

Osteoporosis poses substantial challenges for biomaterials implantation. New approaches to improve bone-implant integration should resolve the fundamental dilemma of inflammation—proper inflammation is required at early stages but should be suppressed later for better healing, especially under osteoporosis. However, precisely switching on and off inflammation around implants in vivo remains unachieved. To address this challenge, a “bridge-burning” coating material that comprises a macrophage-activating glycan covalently crosslinked by a macrophage-eliminating bisphosphonate to titanium implant surface is designed. Upon implantation, the glycan instructs host macrophages to release pro-osteogenic cytokines (“switch-on”), promoting bone cell differentiation. Later, increasingly mature bone cells secrete alkaline phosphatase to cleave the glycan-bisphosphonate complexes from the implant, which in turn selectively kill the proinflammatory macrophages (“switch-off”) that have completed their contribution—hence in the manner of “burning bridges”—to promote healing. In vivo examination in an osteoporotic rat model demonstrates that this coating significantly enhances bone-implant integration (88.4% higher contact ratio) through modulating local inflammatory niches. In summary, a bioresponsive, endogenously triggered, smart coating material is developed to sequentially harness and abolish the power of inflammation to improve osseointegration under osteoporosis, which represents a new strategy for designing immunomodulatory biomaterials for tissue regeneration.     

Engineering DNA-Grafted Quatsomes as Stable Nucleic Acid-Responsive Fluorescent Nanovesicles

The development of artificial vesicles into responsive architectures capable of sensing the biological environment and simultaneously signaling the presence of a specific target molecule is a key challenge in a range of biomedical applications from drug delivery to diagnostic tools. Herein, the rational design of biomimetic DNA-grafted quatsome (QS) nanovesicles capable of translating the binding of a target molecule to amphiphilic DNA probes into an optical output is presented. QSs are synthetic lipid-based nanovesicles able to confine multiple organic dyes at the nanoscale, resulting in ultra-bright soft materials with attractiveness for sensing applications. Dye-loaded QS nanovesicles of different composition and surface charge are grafted with fluorescent amphiphilic nucleic acid-based probes to produce programmable FRET-active nanovesicles that operate as highly sensitive signal transducers. The photophysical properties of the DNA-grafted nanovesicles are characterized and the highly selective, ratiometric detection of clinically relevant microRNAs with sensitivity in the low nanomolar range are demonstrated. The potential applications of responsive QS nanovesicles for biosensing applications but also as functional nanodevices for targeted biomedical applications is envisaged.     

Dual‐Drug Delivery Using Dextran‐Functionalized Nanoparticles Targeting Cardiac Fibroblasts for Cellular Reprogramming

The inability of the heart to recover from an ischemic insult leads to the formation of fibrotic scar tissue and heart failure. From the therapeutic strategies under investigation, cardiac regeneration holds the promise of restoring the full functionality of a damaged heart. Taking into consideration the presence of vast numbers of fibroblasts and myofibroblasts in the injured heart, direct fibroblast reprogramming into cardiomyocytes using small drug molecules is an attractive therapeutic option to replenish the lost cardiomyocytes. Here, a spermine‐acetalated dextran‐based functional nanoparticle is developed for pH‐triggered drug delivery of two poorly water soluble small molecules, CHIR99021 and SB431542, both capable of increasing the efficiency of direct reprogramming of fibroblast into cardiomyocytes. Upon functionalization with polyethylene glycol and atrial natriuretic peptide, the biocompatibility of the nanosystem is improved, and the cellular interactions with the cardiac nonmyocytes are specifically augmented. The dual delivery of the compounds is verified in vitro, and the compounds exerted concomitantly anticipate biological effects by stabilizing β‐catenin (CHIR99021) and by preventing translocation of Smad3 to the nucleus of (myo)fibroblasts (SB431542). These observations highlight the potential of this nanoparticle‐based system toward improved drug delivery and efficient direct reprogramming of fibroblasts into cardiomyocyte‐like cells, and thus, potential cardiac regeneration therapy.     

Functionalized DNA Nanomaterials Targeting Toll-Like Receptor 4 Prevent Bisphosphonate-Related Osteonecrosis of the Jaw via Regulating Mitochondrial Homeostasis in Macrophages

Imbalance of macrophage polarization characterized by an increase in the percentage of pro-inflammatory M1 macrophages and a decrease in anti-inflammatory M2 macrophages is considered a critical pathogenic mechanism of bisphosphonate-related osteonecrosis of the jaws (BRONJ). Because high levels of Toll-like receptor 4 (TLR4) mediates mitochondrial dyshomeostasis in Zoledronic Acid (ZA)-treated M1 macrophages, tetrahedral DNA nanomaterial (TDN)-modified with TLR4-siRNA on each vertex (TDN-TLR4-4siR) with excellent biocompatibility is synthesized. This novel TDN-TLR4-4siR nanomaterial reverses the polarization phenotype imbalance decreasing the percentage of M1 RAW264.7 macrophages. Mitochondrial dynamics analysis shows a shift from short rod-like ultrastructure to elongated shapes with more mitochondrial network continuity in ZA-primed M1 macrophages after treatment with TDN-TLR4-4siR, along with elevated expression of Mfn1 and Mfn2. TDN-TLR4-4siR further reduces intracellular ROS production and restored mitochondrial membrane potential. Furthermore, decreased sequestra formation and accelerated healing of the extraction wound are observed in the TDN-TLR4-4siR group, resulting in decreased incidence of rat BRONJ via reprogramming polarized macrophages. Consequently, this study establishes a novel strategy using TDN-TLR4-4siR nanomaterial to regulate mitochondrial homeostasis of polarized macrophages to prevent BRONJ.     

A Photo-Therapeutic Nanocomposite with Bio-Responsive Oxygen Self-Supplying Combats Biofilm Infections and Inflammation from Drug-Resistant Bacteria

The use of non-antibiotic strategies to combat refractory drug-resistant bacterial infections, especially biofilms and accompanying inflammation, has recently aroused widespread interest. Herein, a photo-therapeutic nanocomposite with bio-responsive oxygen (O₂) self-supplying is introduced by integrating manganese dioxide (MnO₂) nanozymes onto photosensitizer (indocyanine green, ICG)-loaded mesoporous polydopamine nanoparticles (MPDA), namely MI-MPDA NPs. MI-MPDA can activate O₂ generation in the infection microenvironment, thereby effectively alleviating biofilm hypoxia. Under near-infrared light (NIR) irradiation, continuous O₂ supplying further boosts the level of singlet oxygen (¹O₂), enabling robust biofilm elimination through O₂-potentiated photodynamic/photothermal therapy. Interestingly, MI-MPDA down-regulates the factor expression of inflammatory signaling pathways through MnO₂-mediated reactive oxygen species scavenging, which ameliorates the inflammatory condition. Meanwhile, O₂ supplying prevents the M1-phenotype switch of macrophages from the overexpression of hypoxia-inducible factor-1α (HIF-1α), thereby prompting macrophage reprogramming toward pro-regenerative M2-phenotype. In the mouse models of subcutaneous implant-associated infection caused by methicillin-resistant Staphylococcus aureus (MRSA) biofilms and burn infection caused by Pseudomonas aeruginosa biofilms, NIR-irradiated MI-MPDA not only effectively eliminates the formed biofilms, but also alleviates the oxidative stress and accompanying inflammation, and drives the cascade reaction of immunomodulation-wound healing. Overall, this O₂-potentiated photo-therapeutic strategy provides a reliable tool for combating biofilm infections and inflammation from drug-resistant bacteria.     

Spatiotemporal On–Off Immunomodulatory Hydrogel Targeting NLRP3 Inflammasome for the Treatment of Biofilm-Infected Diabetic Wounds

Biofilm-infected diabetic wounds (BIDWs) with hyperglycemia and bacterial colonization are characterized by disordered inflammation and abnormal activation of NLRP3 inflammasome, leading to sustained macrophage M1 polarization and neutrophil extracellular traps (NETs) formation. An immoderate anti-inflammatory treatment that downregulates NLRP3 in turn promotes the persistence of biofilm infections and impairs the healing of BIDWs. Therefore, reconciling biofilm elimination and immune regulation holds the promise of curing BIDWs. Herein, a novel spatiotemporal on–off immunomodulatory therapy (SOIT) is proposed for treating BIDWs through biphasic regulation of NLRP3. Methacrylate gelatin hydrogels (Gel-MA) incorporated with graphene oxide (GO) and metformin-loaded mesoporous silicone nanospheres are synthesized and photo cross-linked to construct a nanocomposite hydrogel (MGO@GM). First, GO nanosheets released from MGO@GM inhibit bacterial biofilm formation and disrupt mature biofilms under near-infrared irradiation. Meanwhile, GO activates the NLRP3 to induce a macrophage-associated proinflammatory response against biofilms. Afterward, with the subsequent degradation of MGO@GM, released metformin reduces local hyperglycemia, downregulates NLRP3, and inhibits NETs formation. Furthermore, repolarized M2 macrophages alleviate the inflammatory microenvironment and promote tissue regeneration. Briefly, this SOIT strategy regulates the NLRP3 and rescues impaired innate immunity to facilitate anti-infection and tissue repair, which provides a new perspective for the future clinical treatment of BIDWs.     

Cardiac computed tomography

Diseases of the heart and blood vessels represent one of the most challenging problems for advanced diagnostic imaging systems. Not only do these diseases represent the major medical problem of our time in terms of death, acute and chronic illness, and disability, but cardiac diagnosis involves complex technical difficulties due to rapid motion and the complex structure of the heart and cardiovascular system. Computerized-tomographic scanning is potentially an ideal cardiac imaging modality since CT is a cross-sectional imaging method with potentially very high resolution. Currently available CT scanners have exposure speeds in the range of 1-5 s, a speed that is inadequate for the majority of cardiovascular imaging applications. Nevertheless, a variety of limited CT scanning techniques have been successfully applied to selected imaging problems. These methods involve the use of contrast media injected into the blood combined with either dynamic CT scanning or gated CT scanning. Currently advanced CT scanners permit visualization of major coronary arteries, imaging of normal and ischemic myocardium, and quantitation of the volumes of the major cardiac chambers. Fast, multiple-slice CT scanners are actively under development. No-motion, electronic scanning using scanning electron-beam techniques represents a promising approach to high-speed fully three-dimensional CT scanning. The CVCT scanner, under development at the University of California, San Francisco, will image up to 8 contiguous slices at a rate of 36-54 images per second. The technical feasibility of the CVCT has been demonstrated using a testbed simulation of the scanning-beam configuration. The completed prototype scanner is expected to be available for testing early in 1983.     

Ultraselective Carbon Nanotubes for Photoacoustic Imaging of Inflamed Atherosclerotic Plaques

Disruption of vulnerable atherosclerotic plaques often leads to myocardial infarction and stroke, the leading causes of morbidity and mortality in the United States. A diagnostic method that detects early-stage high-risk atherosclerotic plaques could prevent these sequelae. The abundant immune cells in the arterial wall, especially inflammatory Ly-6C^hi monocytes and foamy macrophages, are indicative of plaque inflammation, and may be associated with plaque vulnerability. Hence, a new method is sought to develop that specifically targets these immune cells to offer clinically relevant diagnostic information about cardiovascular disease. Ultraselective nanoparticle targeting of Ly-6C^hi monocytes and foamy macrophages and clinically-viable photoacoustic imaging (PAI) are combined in order to precisely and specifically image inflamed plaques ex vivo in a mouse model that mimics human vulnerable plaques histopathologically. Within the plaques, high-dimensional single-cell flow cytometry (13-parameter) shows that the nanoparticles are almost-exclusively taken up by the Ly-6C^hi monocytes and foamy macrophages that heavily infiltrate plaques. PAI identifies inflamed atherosclerotic plaques that display ≈6-fold greater signal compared to controls (P < 0.001) 6 h after intravenous injection of ultraselective carbon nanotubes, with in vivo corroboration via optical imaging. This highly-selective strategy may provide a targeted, noninvasive imaging strategy to accurately identify and diagnose inflamed atherosclerotic lesions.     

Mussel‐Inspired Conductive Cryogel as Cardiac Tissue Patch to Repair Myocardial Infarction by Migration of Conductive Nanoparticles

The engineered cardiac patch (ECP) is a promising strategy to repair infarct myocardium and restore the cardiac function. An ideal ECP should be able to mimic the primary attributes of native myocardium, which includes a high resilience, good cardiomyocyte adhesion, and synchronous contraction. Here, a mussel‐inspired dopamine crosslinker is used to integrate polypyrrole (Ppy) nanoparticles, gelatin‐methyacrylate, and poly(ethylene glycol) diacrylate into a cryogel form. The dopamine crosslinker and Ppy nanoparticles are coordinated to obtain optimal mechanical and superelastic properties for the ECP. The dopamine facilitates the uniform distribution of the Ppy nanoparticles, which migrate and fuse from the scaffold to the surface of the cardiomyocytes, revealing a potential mechanism for restoring infarct myocardium. The incorporated Ppy nanoparticles thus significantly enhance the functionalization of the cardiomyocytes, resulting in excellent synchronous contraction by increasing the expression of α‐actinin and CX‐43. Cardiomyocytes‐loaded ECP can improve the cardiac function in myocardial‐infarction (MI) affected rat models. The results show that the fractional shortening and ejection fraction are elevated by about 50% and that the infarct size is reduced by 42.6%. Collectively, this study highlights an effective cardiac patch based on mussel‐inspired conductive particle adhesion and a superelastic cryogel promising for the restoration of infarcted myocardium.     

YAP-Suppressive Nanodrug Crosslinked Self-Immunoregulatory Polysaccharide Injectable Hydrogel for Attenuating Cardiac Fibrosis to Treat Myocardial Infarction

The cardiac fibrosis caused by excessive deposition of collagen and the fibro-inflammatory cascade reaction severely impedes the cardiac regenerative efficiency after myocardial infarction (MI) so that the onefold treating target is far from satisfying therapeutic efficacy. Herein, a yes-associated protein (YAP)-suppressive nanodrug-crosslinked self-immunoregulatory polysaccharide injectable hydrogel is fabricated for the first time. To this end, cationic liposomes loading YAP inhibitor verteporfin (Lipo-VP) is prepared and coated with oxidized fucoidan (OFu), a unique anti-inflammation polysaccharide, to form anti-fibrotic and immunoregulatory nanodrug (OFu-Lipo-VP). The coated fucoidan itself acts as a reactive oxygen species (ROS) scavenger and inflammation regulator, thus facilitating angiogenesis function by eliciting endogenous vascular endothelial growth factor secretion of macrophages. Then an injectable hydrogel (termed as OFu-Lipo-VP-PGA) is formed through addition reaction between the aldehyde groups of OFu-Lipo-VP and the thiol groups of thiol-modified poly(γ-glutamic acid) (PGA-SH), where the thiol groups can also aid in eliminating ROS. The acute MI models are established and the infarcted male rats are treated with this injectable OFu-Lipo-VP-PGA hydrogel after MI. The outcomes at 28 days post-surgery indicate efficient restoration of cardiac functions and attenuation of cardiac fibrosis. This study opens up a new possibility for MI treatment with immunoregulatory and antifibrotic injectable polysaccharide-based hydrogel.     

Glycopeptide-Based Multifunctional Hydrogels Promote Diabetic Wound Healing through pH Regulation of Microenvironment

Excessive inflammation, bacterial infection, and blocked angiogenesis make diabetic wound healing challenging. Multifunctional wound dressings have several advantages in diabetic wound healing. In addition, the pH regulation of the microenvironment is shown to be a key factor that promotes skin regeneration through cellular immune regulation. However, few reports have focused on the development of functional dressings with the ability to regulate the pH microenvironment and promote diabetic wound healing. This study presents a novel approach for regulating the pH microenvironment of diabetic wound sites using a glycopeptide-based hydrogel consisting of modified hyaluronic acid and poly(6-aminocaproic acid). This hydrogel forms a network through Schiff base interactions and metal complexation, which suppresses inflammation and accelerates angiogenesis during wound healing. Hydrogels not only have adequate mechanical properties and self-healing ability but can also support tissue adhesion. They can also promote the secretion of inducible cAMP early repressor, which promotes the polarization of macrophages toward the M2 type. The in vivo results confirm that hydrogel promotes diabetic wound repair and skin regeneration by exerting rapid anti-inflammatory effects and promoting angiogenesis. Therefore, this hydrogel system represents an effective strategy for treating diabetic wounds.     

Ultra-Histocompatible and Electrophysiological-Adapted PEDOT-Based Hydrogels Designed for Cardiac Repair

Currently, although conducting polymers have exhibited potential electrophysiological modulation, designing bioinspired ultra-histocompatible conducting polymers remains a long-standing challenge. Moreover, the water dispersibility, conductivity, and biocompatibility of conducting polymers are incompatible, which restricts their application in tissue engineering. Herein, a multilevel template dispersion strategy is presented to produce poly(3,4-ethylenedioxythiophene):(dextran sulfate/carboxymethyl chitosan) (PEDOT:(DSS/CMCS)) with biocompatibility superior to that of commercial poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) without sacrificing processability and conductivity. The PEDOT:(DSS/CMCS) and oxidized dextran solutions form an injectable PEDOT-based hydrogel (PDCOH) mediated by dynamic covalent imine bonds under mild conditions. The PDCOH has a tissue-matched modulus and conductivity to adapt to the mechanical environment of dynamic tissue and modulate fibrosis-induced electrical decoupling. The PDCOH combined with adipose-derived stem cells demonstrates superior cardiac repair effects over cell suspensions and nonconductive hydrogels, inhibiting ventricular remodeling, reducing fibrous scarring, promoting vascular regeneration, and restoring electrophysiological and pulsatile functions.     

Dual Targeted Immunotherapy via In Vivo Delivery of Biohybrid RNAi‐Peptide Nanoparticles to Tumor‐Associated Macrophages and Cancer Cells

Lung cancer is associated with very poor prognosis and considered one of the leading causes of death worldwide. Here, highly potent and selective biohybrid RNA interference (RNAi)‐peptide nanoparticles (NPs) are presented that can induce specific and long‐lasting gene therapy in inflammatory tumor associated macrophages (TAMs), via an immune modulation of the tumor milieu combined with tumor suppressor effects. The data here prove that passive gene silencing can be achieved in cancer cells using regular RNAi NPs. When combined with M2 peptide–based targeted immunotherapy that immuno‐modulates TAMs cell population, a synergistic effect and long‐lived tumor eradication can be observed along with increased mice survival. Treatment with low doses of siRNA (ED₅₀ 0.0025–0.01 mg kg^?1) in a multi and long‐term dosing system substantially reduces the recruitment of inflammatory TAMs in lung tumor tissue, reduces tumor size (≈95%), and increases animal survival (≈75%) in mice. The results here suggest that it is likely that the combination of silencing important genes in tumor cells and in their supporting immune cells in the tumor microenvironment, such as TAMs, will greatly improve cancer clinical outcomes.     

Recent Advances in Electrospun Nanofibrous Scaffolds for Cardiac Tissue Engineering

Cardiovascular diseases remain the leading cause of human mortality worldwide. Some severe symptoms, including myocardial infarction and heart failure, are difficult to heal spontaneously or under systematic treatment due to the limited regenerative capacity of the native myocardium. Cardiac tissue engineering has emerged as a practical strategy to culture functional cardiac tissues and relieve the disorder in myocardium when implanted. In cardiac tissue engineering, the design of a scaffold is closely relevant to the function of the regenerated cardiac tissues. Nanofibrous materials fabricated by electrospinning have been developed as desirable scaffolds for tissue engineering applications because of the biomimicking structure of protein fibers in native extra cellular matrix. The versatilities of electrospinning on the polymer component, the fiber structure, and the functionalization with bioactive molecules have made the fabrication of nanofibrous scaffolds with suitable mechanical strength and biological properties for cardiac tissue engineering feasible. Here, an overview of recent advances in various electrospun scaffolds for engineering cardiac tissues, including the design of advanced electrospun scaffolds and the performance of the scaffolds in functional cardiac tissue regeneration, is provided with the aim to offer guidance in the innovation of novel electrospun scaffolds and methods for improving their potential for cardiac tissue engineering applications.     

Stimuli Responsive Delivery Vehicles for Cardiac Microtissue Transplantation

Cell transplantation has emerged as the most promising therapy for restoring the scarred myocardium in the treatment of heart failure. However, clinical efficacy of (stem) cell therapies is still limited by poor retention rate and survival of injected cells in the ischemic tissue. Here we present a new strategy to deliver microtissues in the treatment of heart dysfunction in order to improve the retention, survival, and integration of the delivered cells. For this purpose, we developed stimuli responsive biodegradable polymer constructs consisting of a thin film of thermosensitive hydrogel coupled to a thin film of non‐responsive polymer. Due to the temperature responsive swelling behavior of the hydrogel layer, the bilayer polymer constructs can roll or unroll at will. Therefore they can potentially be used for efficient encapsulation and protection of cell clusters during delivery, while under physiological conditions, the constructs, named cell wraps, can unroll and expose the delivered microtissue to the ischemic tissue.