Preparation and Characterization of Molecularly Imprinted Polymeric Nanoparticles for Atrial Natriuretic Peptide (ANP)

Natriuretic peptide receptor A (NPRA), the receptor for the cardiac hormone atrial natriuretic peptide (ANP), is expressed abundantly on cancer cells and disruption of ANP‐NPRA signaling inhibits tumor burden and metastasis. Since antagonists of NPRA signaling have not provided reproducible results, we reason that a synthetic neutralizing antibody to ANP, which has high selectivity and affinity for ANP, can be used to regulate ANP levels and attenuate NPRA signaling. In this study, we prepare molecularly imprinted polymeric nanoparticles (MIPNPs) for ANP using a short peptide of ANP as the template and determine their binding affinity and selectivity. The MIPNPs are prepared by precipitation polymerization using NH₂–SLRRSS–CONH₂, which is a short peptide from ANP, as a template, methacrylic acid and N‐isopropylacrylamide as functional monomers, and bis‐acrylamide as a crosslinker. The average diameters of the MIPNPs and of non‐imprinted nanoparticles (NIPNPs) in water are 215.8 ± 4.6 nm and 197.7 ± 3.1 nm respectively. The binding‐isotherm analysis shows that the MIPNPs have a much‐higher binding affinity for the template peptide and ANP than the NIPNPs. Scatchard analysis gives an equilibrium dissociation constant, K_d, of 7.3 × 10^?6 M with a binding capacity of 106.7 μmol g^?1 for the template peptide and a K_d of 7.9 × 10^?6 M with a binding capacity of 36.0 μmol g^?1 for the ANP. Measurements of the binding kinetics reveal that MIPNPs reach protein‐adsorption equilibrium in 30 min. The MIPNPs are found to have a high specificity for ANP with little affinity for BSA or scrambled ANP peptide. The MIPNPs also recognize and adsorb ANP in cell‐culture medium spiked with ANP and in human plasma. Taken together, these results indicate that the MIPNPs have a high affinity and selectivity for ANP and can be used as a synthetic antibody for modulating ANP‐NPRA signaling in cancers.     

Tumor Microenvironment Responsive Drug‐Dye‐Peptide Nanoassembly for Enhanced Tumor‐Targeting,Penetration, and Photo‐Chemo‐Immunotherapy

Nanomedicine constructed by therapeutics has unique and irreplaceable advantages in biomedical applications, especially in drug delivery for cancer therapy. The strategy, however, used to construct the therapeutics‐based nanomedicines with tumor microenvironmental factor responsiveness is still sophisticated. In this study, an easy‐operating procedure is used to construct a therapeutics‐based nanosystem with active tumor‐targeting, enhanced penetration, and stimuli‐responsive drug release behavior as well as programmed cell death‐1/programmed cell death‐ligand 1 (PD‐1/PD‐L1) blockading mediated immunomodulation to enhance tumor immunotherapy. The matrix metalloproteinase‐2 responsive peptide with the existence of Lyp‐1 sequence contributes to the success of active tumor‐targeting and the enhancement of the penetration of the nanoparticles in tumor tissue. The obtained nanosystem strikingly inhibits the primary tumor growth in the first 24 h (more than 97.5% of tumor cells are inhibited), and total inhibition can be achieved with the combination of photothermal therapy. IR820, which is served as the carrier for the therapeutics, is used as a photosensitizer for photothermal therapy. The progress and aggression of distal tumor has further been alleviated by a d ‐peptide which is an antagonist for PD‐1/PD‐L1 blockage. Therefore, a therapeutics‐constructed multifunctional nanosystem is provided to realize a combinational therapeutic strategy to enhance the therapeutic outcome.     

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.     

Targeted Delivery of Apoptotic Cell-Derived Nanovesicles prevents Cardiac Remodeling and Attenuates Cardiac Function Exacerbation

The modulation of inflammatory responses plays an important role in the pathobiology of cardiac failure. In a natural healing process, the ingestion of apoptotic cells and their apoptotic bodies by macrophages in a focal lesion result in resolution of inflammation and regeneration. However, therapeutic strategies to enhance this natural healing process using apoptotic cell-derived biomaterials have not yet been established. In this study, apoptotic bodies-mimetic nanovesicles derived from apoptotic fibroblasts (ApoNVs) conjugated with dextran and ischemic cardiac homing peptide (CHP) (ApoNV-DCs) for ischemia-reperfusion (IR)-injured heart treatment are developed. Intravenously injected ApoNV-DCs actively targeted the ischemic myocardium via conjugation with CHP, and are selectively phagocytosed by macrophages in an infarcted myocardium via conjugation with dextran. ApoNV-DCs polarized macrophages from the M1 to M2 phenotype, resulting in the attenuation of inflammation. Four weeks after injection, ApoNV-DCs attenuated cardiac remodeling, preserved blood vessels, and prevented cardiac function exacerbation in IR-injured hearts. Taken together, the findings may open a new avenue for immunomodulation using targeted delivery of anti-inflammatory nanovesicles that can be universally applied for various inflammatory diseases.     

Light-Controlled Nanosystem with Size-Flexibility Improves Targeted Retention for Tumor Suppression

Although great promise has been achieved with nanomedicines in cancer therapy, limitations are still encountered, such as short retention time in the tumor. Herein, a nanosystem that can modulate the particle size in situ by near-infrared (NIR) light is self-assembled by cross-linking the surface-modified poly(lactic-co-glycolic acid) from the up-conversion nanoparticle with indocyanine green and doxorubicin–nitrobenezene–polyethylene glycol (DOX–NB–PEG). The nanosystem with its small size (≈100 nm) achieves better tumor targeting, while the PEG on the surface of the nanosystem can effectively shield the adsorption of proteins during blood circulation, maintaining a stable nanostructure and achieving good tumor targeting. Moreover, the nanosystem at the tumor realizes the rapid shedding of PEG on its surface by NIR irradiation, and the enhanced cellular uptake. At the same time, aggregation occurs inside the nanosystem to form bigger particles (≈600 nm) in situ, prolonging the retention time at the tumor and producing enhanced targeted therapeutic effects. In vitro data show higher cellular uptake and a higher rate of apoptosis after irradiation, and the in vivo data prove that the nanosystem have a longer residence time at the tumor site after NIR irradiation. This nanosystem demonstrates an effective therapeutic strategy in targeted synergistic tumors.     

Cobweb-Inspired Microenvironment-Targeting Nanosystem with Sequential Multiple-Stage Stimulus-Response Capacity for Ischaemic Tissue Repair

Myocardial ischaemia is pathologically complicated; various changes in intracellular and extracellular microenvironments make it essential to develop a smart drug system with multiple stimulus responses to adapt to the complex process. Inspired by the cobweb, this study designs a microreticular nanosystem that adheres to tissue and is sequentially responsive to multiple stimuli in the ischaemic microenvironment. The nanosystem is fabricated from hyaluronic acid (HA), ROS-responsive B-PDEA, and hypoxia-sensitive VEGF-expressing plasmids (EPODNA) through electrostatic interactions. After intramyocardial injection, the tissue-adhesive property of the nanosystem will significantly decrease its acute loss from the injection site. Extracellularly, the microreticular nanosystem first responds to activated hyaluronidase (hyal), releasing HA for microenvironment regulation and B-PDEA/DNA nanoparticles (NP) with high transfection efficiency for cardiac cells. Intracellularly, ROS sequentially induced B-PDEA/DNA NP dissociation, consuming some ROS to attenuate oxidative stress and releasing DNA to promote its expression. Meanwhile, local hypoxia significantly activates VEGF expression in plasmids for myocardial revascularization and repair. The function of the microreticular nanosystem is systematically evaluated in vitro. In a rat model of myocardial infarction, treatment with the microreticular nanosystem significantly promotes functional and structural improvements. Collectively, the study provides a promising smart nanosystem to promote tissue repair after complex damage.     

In Situ Enzyme-Induced Self-Assembly of Antimicrobial-Antioxidative Peptides to Promote Wound Healing

Antimicrobial peptides (AMPs) with dual intrinsic antibacterial and antioxidative functions have emerged as promising choice to cure infected wound. However, the most widely applied approach to endow AMPs with antioxidative function is to combine with antioxidative moieties, which may affect the spatial structure and physiological stability of AMPs. Herein, a new type of AMPs with inherent desired stability, antibacterial activity, and reactive oxygen species (ROS) scavenging is developed to effectively heal the infected wound. This formulation is in situ formed at wound site by tyrosinase-triggered oxidation and self-assembly of lyophilized antimicrobial peptide Trp-Arg-Trp-Arg-Trp-Tyr, providing enhanced stability and a fourfold and sevenfold increasement in antibacterial efficiency against E. coli and S. aureus compared to peptide monomers. The antimicrobial peptide is first oxidized and then assembled into nanoparticles. The melanin-like structure has been demonstrated with efficient antioxidant properties, and the experimental data show that peptide nanoparticles to scavenge superoxide radicals, hydroxyl radicals, and H₂O₂. In vivo experiments confirmed that peptide nanoparticles effectively heal infected wounds and obviously reduce ROS. Overall, the research provides a new approach to formulating antimicrobial peptides to treat wound with high healing efficiency.     

Injectable Scaffolds for In Vivo Programmed Macrophages Manufacture and Postoperative Cancer Immunotherapy

Cancer recurrence and metastasis after surgical resection is a vital reason of treatment failure. The modification of immune cells through implanted biomaterials is a promising postoperative immunotherapy. Herein, an injectable hydrogel scaffold loaded with engineered exosome mimetics that in vivo recruits and programs endogenous macrophages into M1 binding with anti-CD47 antibody (M1-aCD47 macrophages) for postoperative cancer immunotherapy is developed. Briefly, M1 macrophages-derived exosome mimetics co-modified with vesicular stomatitis virus glycoprotein (VSV-G) and aCD47 (V-M1EM-aCD47) are encapsulated in injectable chitosan hydrogel. Such hydrogel recruits inherent macrophages in situ and releases V-M1EM-aCD47 that programs M2 to M1-aCD47 macrophages. M1-aCD47 macrophages own dual-functions of tumor-homing and enhanced phagocytosis. They can actively target to tumor cells for delivery of aCD47 that blocks the “don't eat me” signal, thereby promoting phagocytosis of macrophages to cancer cells. Furthermore, V-M1EM-aCD47 hydrogel implanted into resection site of 4T1 breast tumor inhibits tumor recurrence and metastasis by phagocytosis of M1-aCD47 macrophages and T cell-mediated immune responses. The findings demonstrate that biomaterials can be designed in vivo to program inherent macrophages, thereby activating the innate and adaptive immune systems for prevention of postoperative tumor recurrence and metastasis.     

Fabrication of Glyco‐Metal‐Organic Frameworks for Targeted Interventional Photodynamic/Chemotherapy for Hepatocellular Carcinoma through Percutaneous Transperitoneal Puncture

Hepatocellular carcinoma (HCC) causes high morbidity and mortality due to a lack of adequate treatments. Cancer treatments have benefited from nanotechnology approaches that integrate multimodal synergistic therapies. A synergistic, minimally invasive strategy of interventional photodynamic therapy (IPDT) and chemotherapy for HCC treatment through percutaneous transperitoneal puncture is disclosed that is based on photosensitive porphyrinic galactose‐modified metal‐organic frameworks (PCN‐224) first used as hepatic targeting and encapsulated with anticancer drug doxorubicin (DOX@Gal‐PCN‐224). Real‐time imaging reveals the effective accumulation of the integrated nanosystem in the HCC cells and tumor tissues due to hepatic targeting. Evaluation of the anti‐tumor efficiency of this nanosystem on orthotopic transplantation tumors with the aid of minimally invasive intervention shows a tumor inhibition rate of 98%. The synergistic effects induce high‐level cell apoptosis and tissue necrosis in vitro and in vivo. This bimodal IPDT/chemotherapy strategy holds great potential in the clinical treatment for HCC.     

Targeting of CXCR1 on Osteosarcoma Circulating Tumor Cells and Precise Treatment via Cisplatin Nanodelivery

Metastasis and chemotherapy resistance are the key factors affecting the effectiveness of osteosarcoma (OS) treatments. CXCR1 overexpression is found to be closely related to chemotherapy resistance and anoikis resistance in OS cell subtypes with high metastasis potential. Further study demonstrates that CXCR1 is highly expressed on circulating tumor cell (CTC)‐derived cells with cancer stem cell characteristics. Then, a CXCR1 targeting peptide is designed and synthesized to competitively inhibit the IL‐8/CXCR1 pathway and to improve the cisplatin sensitivity of CTCs. Fluorescence‐labeled magnetic nanoparticles (NPs) with pH‐responsive cisplatin release are fabricated and linked with the CXCR1 targeting peptide (Cis@MFPPC). Results demonstrate that CTC survival could be inhibited effectively by the targeting nanoparticles in vivo. Cis@MFPPC can also inhibit OS growth and pulmonary metastasis in an orthotopic model and patient‐derived tumor xenograft model. This study verifies the clinical significance of CXCR1 as a therapeutic target and provides a drug delivery NP system for precise treatment of OS.     

Mesoporous Polydopamine Carrying Manganese Carbonyl Responds to Tumor Microenvironment for Multimodal Imaging‐Guided Cancer Therapy

Multifunctional nanodrugs integrating multiple therapeutic and imaging functions may find tremendous biomedical applications. However, the development of a simple yet potent theranostic nanosystem with a high payload and microenvironment responsiveness enhancing imaging‐guided cancer therapy is still a great challenge. Herein, a kind of MnCO‐entrapped mesoporous polydopamine nanoparticles are developed, which reach a 1.5 mg payload per gram carrier and exhibit marked theranostic capability through effective CO/Mn²⁺ generation and photothermal conversion inside the H⁺ and H₂O₂‐enriched tumor microenvironment, for a magnetic resonance/photoacoustic bimodal imaging‐guided tumor therapy. The multifunctional nanosystem exhibits a biocompatibility highly desirable for in vivo application and superior performance in inhibiting tumor growth and recurrence via combination CO and photothermal therapy.     

Antibody Engineered Platelets Attracted by Bacteria-Induced Tumor-Specific Blood Coagulation for Checkpoint Inhibitor Immunotherapy

Bacteria can act as a promising anti-tumor platform due to their specific targeting capacity to the tumor microenvironment. In this study, it is discovered that intravenous administration of Escherichia coli TOP10 induces rapid and intense blood coagulation in tumor tissues instead of normal tissues. It is demonstrated that E. coli TOP10 can act as an activator of a coagulation cascade to trigger abnormal hemorrhage, blood coagulation, and inflammation with abundant macrophages recruitment in tumors. In addition, the recruited macrophages are principally polarized by lipopolysaccharide in the bacterial wall to the anti-tumor M1-like phenotype. Based on the above finding, coagulation-tropism blood platelets decorated with CD47 antibodies (Anti-CD47), which possess tropism for bacteria-treated tumors are further prepared. As a result, Anti-CD47 blocks the “don't eat me” signal from tumor cells, consequently promoting the phagocytosis of polarized M1-like phenotype macrophages for tumor cells. This manipulation of local blood coagulation in tumors may find great potential for accurately delivering immune checkpoint inhibitors and facilitating tumor immunotherapy.     

A Sequentially Triggered Nanosystem for Precise Drug Delivery and Simultaneous Inhibition of Cancer Growth,Migration, and Invasion

The rational design of cancer‐targeted and bioresponsive drug delivery vehicles can enhance the anticancer efficacy of conventional chemotherapeutics and reduce their adverse side effects. However, the complexity of precise delivery and the ability to trigger drug release in specific tumor sites remain a challenging puzzle. Here, a sequentially triggered nanosystem composed of HER2 antibody with disulfide linkage as a surface decorator (HER2@NPs) is constructed for precise drug delivery and the simultaneous inhibition of cancer growth, migration, and invasion. The nanosystem actively accumulates in cancer cells, undergoes self‐immolative cleavage in response to biological thiols, and is degraded to form small nanoparticles. After internalization by receptor‐mediated endocytosis, the nanoparticles further disassemble under acidic conditions in the presence of lysozymes and cell lysates, leading to sequentially triggered drug release. The released payload triggers overproduction of reactive oxygen species and activates p53 and MAPKs pathways to induce cancer cell apoptosis. Moreover, HER2@NPs markedly suppress the migration and invasion of human bladder cancer cells at nontoxic concentrations. HER2@NPs demonstrate potent in vivo anticancer efficacy, but show no obvious histological damage to the major organs. Taken together, this study provides a valid tactic for the rational design of sequentially triggered nanosystems for precise drug delivery and cancer therapy.     

Optomagnetic Nanoplatforms for In Situ Controlled Hyperthermia

Magnetic nanoparticles (M:NPs) are unique agents for in vivo thermal therapies due to their multimodal capacity for efficient heat generation under optical and/or magnetic excitation. Nevertheless, their transfer from laboratory to the clinic is hampered by the absence of thermal feedback and by the influence that external conditions (e.g., agglomeration and biological matrix interactions) have on their heating efficiency. Overcoming these limitations requires, first, the implementation of strategies providing thermal sensing to M:NPs in order to obtain in situ thermal feedback during thermal therapies. At the same time, M:NPs should be modified so that their heating efficiency will be maintained independently of the environment and the added capability for thermometry. In this work, optomagnetic hybrid nanostructures (OMHSs) that simultaneously satisfy these two conditions are presented. Polymeric encapsulation of M:NPs with neodymium‐doped nanoparticles results in a hybrid structure capable of subtissue thermal feedback while making the heating efficiency of M:NPs independent of the medium. The potential application of the OMHSs herein developed for fully controlled thermal therapies is demonstrated by an ex vivo endoscope‐assisted controlled intracoronary heating experiment.     

Effective PEGylation of Iron Oxide Nanoparticles for High Performance In Vivo Cancer Imaging

A practical and effective strategy for synthesizing PEGylated superparamagnetic iron oxide nanoparticles (SPIONs) is established. In this strategy, poly(acrylic acid) (PAA) is combined with SPIONs via multiple coordination between the carboxylic groups of PAA and SPIONs, which introduces abundant carboxylic groups, then, α,ω‐diamino PEG is linked to SPIONs via the amidation of the carboxylic groups. The synthesized PEGylated SPIONs exhibit no cytotoxicity and high resistance to phagocytosis by macrophages in vitro as well as low uptake by the liver and spleen in vivo, which makes the SPIONs highly efficient in tumor imaging by magnetic resonance imaging (MRI) at a relatively low dose of SPIONs. These outstanding properties are largely due to the significant shielding effect of the dense PEG coating as well as the net neutral surface of the PEGylated SPIONs in physiological conditions. In summary, the PEGylated SPIONs prepared by this strategy exhibit great application potential in tumor imaging as MRI contrast agents targeting through enhanced permeability and retention (EPR) effect.     

Enhanced Penetration and Retention of CuS-Based Nanosystem Through NIR Light and In Situ Enzyme Response for Improved Tumor Therapy

The efficient way to increase the therapeutic efficacy of nanomedicines is by encouraging the penetration and enhancing the retention of nanoparticles at the tumor site. However, it is a serious dilemma that small nanoparticles can penetrate deep into the tumor tissue but easily be cleared into the surrounding tissues. In order to solve this dilemma, a smart nanosystem is created to address this problem, ensuring both the effective penetration of tiny nanoparticles (NPs) and their appropriate retention at the tumor site. CuS NPs that is modified with peptides are prepared facilely, and can aggregate in situ through the intermolecular crosslinking reaction catalyzed by the transglutaminase (TGase) abundantly expressed at the tumor site, resulting in an outstanding photothermal effect for tumor therapy. Upon NIR irradiation, the photothermal effect of CuS-K and CuS-Q induced the disintegration of liposomes and prompted the release of CuS-K, CuS-Q, and indocyanine green (ICG). Simultaneously, CuS-K and CuS-Q aggregated under the catalysis of TGase after being internalized by tumor cells to enhance photothermal therapy. The current study provides valuable inspiration to design nanomedicines with prolonged circulation time in the blood system, better penetration, and retention at the tumor site, and multimodal tumor therapy to achieve the desired therapeutic efficacy.     

Biocompatible,Uniform, and Redispersible Mesoporous Silica Nanoparticles for Cancer‐Targeted Drug Delivery In Vivo

Engineering multifunctional nanocarriers for targeted drug delivery shows promising potentials to revolutionize the cancer chemotherapy. Simple methods to optimize physicochemical characteristics and surface composition of the drug nanocarriers need to be developed in order to tackle major challenges for smooth translation of suitable nanocarriers to clinical applications. Here, rational development and utilization of multifunctional mesoporous silica nanoparticles (MSNPs) for targeting MDA‐MB‐231 xenograft model breast cancer in vivo are reported. Uniform and redispersible poly(ethylene glycol)‐incorporated MSNPs with three different sizes (48, 72, 100 nm) are synthesized. They are then functionalized with amino‐β‐cyclodextrin bridged by cleavable disulfide bonds, where amino‐β‐cyclodextrin blocks drugs inside the mesopores. The incorporation of active folate targeting ligand onto 48 nm of multifunctional MSNPs (PEG‐MSNPs48‐CD‐PEG‐FA) leads to improved and selective uptake of the nanoparticles into tumor. Targeted drug delivery capability of PEG‐MSNPs48‐CD‐PEG‐FA is demonstrated by significant inhibition of the tumor growth in mice treated with doxorubicin‐loaded nanoparticles, where doxorubicin is released triggered by intracellular acidic pH and glutathione. Doxorubicin‐loaded PEG‐MSNPs48‐CD‐PEG‐FA exhibits better in vivo therapeutic efficacy as compared with free doxorubicin and non‐targeted nanoparticles. Current study presents successful utilization of multifunctional MSNP‐based drug nanocarriers for targeted cancer therapy in vivo.     

Dual‐Targeting to Cancer Cells and M2 Macrophages via Biomimetic Delivery of Mannosylated Albumin Nanoparticles for Drug‐Resistant Cancer Therapy

Multidrug resistance (MDR) is an issue that is not only related to cancer cells but also associated with the tumor microenvironments. MDR involves the complicated cancer cellular events and the crosstalk between cancer cells and their surroundings. Ideally, an effective system against MDR cancer should take dual action on both cancer cells and tumor microenvironments. The authors find that both the drug‐resistant colon cancer cells and the protumor M2 macrophages highly express two nutrient transporters, i.e., secreted protein acidic and rich in cysteine (SPARC) and mannose receptors (MR). By targeting SPARC and MR, a system can act on both cancer cells and M2 macrophages. Herein the authors develop a mannosylated albumin nanoparticles with coencapsulation of different drugs, i.e., disulfiram/copper complex (DSF/Cu) and regorafenib (Rego). The results show that combination therapy of DSF/Cu and Rego efficiently inhibits the growth of drug‐resistant colon tumor, and the combination has not been reported yet for use in anticancer treatment. The system significantly improves the treatment outcomes in the animal model bearing drug‐resistant tumors. The therapeutic mechanisms involve enhanced apoptosis, upregulation of intracellular ROS, anti‐angiogenesis, and tumor‐associated macrophage “re‐education.” This strategy is characterized by dual targeting to and the simultaneous action on cancer cells and M2 macrophages, with biomimetic codelivery of a novel drug combination.     

In vivo validation of longitudinal-circumferential area change ratio to estimate myofiber shortening in the heart

The aim of this paper was to validate area change ratio (%AC) against myofiber shortening (%λ(f)) in the heart in vivo. %AC is emerging as a mechanical index that may approximate %λ(f) by incorporating both circumferential and longitudinal shortening. However, the physiological significance of % AC remains unclear. We studied the time course of %AC in the anterior midleft ventricular wall of normal canine heart in vivo (n = 14) during atrial pacing over the entire cardiac cycle using transmurally implanted markers and biplane cineradiography (8 ms/frame). %AC was calculated as the myocardial area change relative to the elemental material area on the circumferential-longitudinal plane at the reference configuration (=end diastole). %AC was compared with %λ(f) that was determined from the transmural fiber orientation directly measured in the heart tissue. The time course of both %AC and %λ(f) was determined in the subepicardial, midwall, and subendocardial layers. The time course of %AC and %λ(f) was significantly different, and the difference was more pronounced towards the endocardium. %AC consistently overestimated %λ(f). The timing of the peak %AC was significantly delayed compared to that of the peak %λ(f). We conclude that %AC is significantly different from %λ(f) both in magnitude and timing in vivo. %AC overestimates %λ(f), and the overestimation is worse toward the endocardial layers. This may be a potentially important limitation when applying %AC to optimization and responder identification for cardiac resynchronization therapy.     

Rational Engineering of a Mitochondrial-Mimetic Therapy for Targeted Treatment of Dilated Cardiomyopathy by Precisely Regulating Mitochondrial Homeostasis

Dilated cardiomyopathy (DCM) is a leading cause of heart failure and the most common indication for heart transplantation. Currently, there is still an unmet clinical need in effective therapies for DCM. Herein a mitochondrial-mimetic therapy capable of efficiently targeting the heart, cardiomyocytes, and myocardial mitochondria as well as effectively regulating mitochondrial homeostasis for targeted treatment of DCM is reported. A bioactive conjugate TPT is first synthesized by integrating three functional moieties onto a scaffold, which can assemble into small-size nanomicelles (i.e., TPTN). Intravenously delivered TPTN efficiently accumulates in the heart and mainly localizes in cardiomyocytes and myocardial mitochondria of DCM mice, thereby alleviating DCM. Mechanistically, TPTN inhibits intracellular oxidative stress, alleviates mitochondrial injury, improves mitochondrial dynamics, regulates mitochondrial oxidative phosphorylation, and reduces calpain-1 and NLRP3 inflammasome activation, thus restoring mitochondrial homeostasis and inhibiting adverse cardiac remodeling. By packaging TPTN into outer mitochondrial membrane-derived vesicles, a mitochondrial-mimetic therapy is engineered, which displays significantly enhanced three-level targeting capability to the heart, cardiac cells, and myocardial mitochondria, thereby affording notably potentiated therapeutic effects in DCM mice. Accordingly, the three-level targeting mimetics is promising for targeted treatment of DCM. The findings provide new insight into rational design of precision therapies for mitochondrial dysfunction-associated diseases.