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The senescence of aortic valve interstitial cells (VICs) plays a critical role in the progression of calcific aortic valve disease (CAVD). However, the precise mechanisms underlying the senescence of VICs remain unclear, demanding the identification of a novel target to mitigate this process. Previous studies have highlighted the anti‐aging potential of morusin. Thus, this study aimed to explore the therapeutic potential of morusin in CAVD. Cellular experiments reveal that morusin effectively suppresses cellular senescence and cause a shift toward osteogenic differentiation of VICs in vitro. Mechanistically, morusin activate the Nrf2‐mediated antiaging signaling pathway by downregulating CCND1 expression and aiding Keap1 degradation through Trim 25. This activation lead to the upregulated expression of antioxidant genes, thus reducing reactive oxygen species production and thereby preventing VIC osteogenic differentiation. In vivo experiments in ApoE−/− mice on a high‐fat Western diet demonstrate the positive effect of morusin in mitigating aortic valve calcification. These findings emphasize the antiaging properties of morusin and its potential as a therapeutic agent for CAVD. [ABSTRACT FROM AUTHOR]

A versatile tumor‐targeting stimuli‐responsive theranostic platform for peritoneal metastases of colorectal cancer is proposed in this work for tumor tracking and photothermal‐enhanced chemotherapy. A quenched photosensitizer ("off" state) is developed and escorted into a tumor‐targeting oxaliplatin‐embedded micelle. Once reaching the tumor cell, the micelle is clasped to release free oxaliplatin, as well as the "off" photosensitizer, which is further activated ("turned‐on") in the tumor reducing microenvironment to provide optical imaging and photothermal effect. The combined results from hyperthermia‐enhanced chemotherapy, deep penetration, perfused O2, and the leveraged GSH‐ROS imbalance in tumor cells are achieved for improved antitumor efficacy and reduced systematic toxicity. [ABSTRACT FROM AUTHOR]

Lack of tumor‐infiltration lymphocytes (TILs) and resistances by overexpressed immunosuppressive cells (principally, myeloid‐derived suppressor cells (MDSCs)) in tumor milieu are two major challenges hindering the effectiveness of immunotherapy for "immune‐cold" tumors. In addition, the natural physical barrier existing in solid cancer also limits deeper delivery of drugs. Here, a tumor‐targeting and light‐responsive‐penetrable nanoplatform (Apt/PDGs^s@pMOF) is developed to elicit intratumoral infiltration of cytotoxic T cells (CTLs) and reeducate immunosuppressive microenvironment simultaneously. In particular, porphyrinic metal–organic framework (pMOF)–based photodynamic therapy (PDT) induces tumor immunogenic cell death (ICD) to promote CTLs intratumoral infiltration and hot "immune‐cold" tumor. Upon being triggered by PDT, the nearly 10 nm adsorbed drug‐loaded dendrimer de‐shields from the nanoplatform and spreads into the deeper tumor, eliminating MDSCs and reversing immunosuppression, eventually reinforcing immune response. Meanwhile, the designed nanoplatform also has a systemic MDSC inhibition effect and moderate improvement of overall antitumor immune responses, resulting in effective suppression of distal tumors within less significant immune‐related adverse effects (irAEs) induced. [ABSTRACT FROM AUTHOR]

Abstract: Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive malignancy with a five year survival rate of <5%. The aberrant expression of extracellular matrix (ECM) in the tumor stroma forms a compact physical barrier, which that leads to insufficient extravasation and penetration of nanosized therapies. To overcome the severe resistance of PDAC to conventional therapies, a sequentially triggered nanoparticle (aptamer/cell‐penetrating peptide‐camptothecin prodrug, i.e., Apt/CPP‐CPTD NPs) with tumor penetration and intelligent drug release profile is designed. An ECM component (tenescin‐C) targeting aptamer (GBI‐10) is modified onto stroma‐permeable cell‐penetrating peptide (CPP) for the in vivo CPP camouflage and PDAC‐homing. In PDAC stroma, tenascin‐C can detach GBI‐10 from CPP and exposed CPP can facilitate further PDAC penetration and tumor cell endocytosis. After being endocytosed into PDAC cells, intracellular high redox potential can further trigger controlled chemodrug release. Apt/CPP‐CPTD NPs show both deep penetration in vitro 3D PDAC spheroids and in vivo tumor sections. The relatively mild in vitro cytotoxicity and excellent in vivo antitumor efficacy proves the improved PDAC targeting drug delivery and decreased systemic toxicity. The design of ECM‐redox sequentially triggered stroma permeable NPs may provide a practical approach for deep penetration of PDAC and enhanced drug delivery efficacy. [ABSTRACT FROM AUTHOR]

Tumor‐associated macrophages (TAMs) constitute over 50% of the number of cells within the tumor, playing a major role in tumor progression and invasion. Remodeling the tumor immune microenvironment by modulating TAM polarization has been emerging as a new and promising therapeutic strategy. However, the high interstitial fluid pressure and dense extracellular matrix lead to insufficient penetration of nanosized therapies. To overcome this dilemma, an acid‐triggered size‐changeable nanoparticle (aptamer/acid sensitive linker crosslinked DGL/zoledronic acid, i.e., Apt@(DGL‐ZA)n NPs) with effective tumor distribution, extravasation, and penetration is designed. Dendrigraft poly‐L‐lysines (DGLs) which can induce tumor autophagy as mimics of natural abnormal proteins are crosslinked via a mild‐acid‐responsive linker (1,6‐bis(4‐formylbenzoyloxy) hexane). Long circulation property and tumor penetration are achieved simultaneously by catching DGLs in neutral pH while releasing them in the tumor's pH, like dandelion seeds in midair. The macrophage conditioning agent zoledronic acid (ZA) is loaded on DGLs by the charge attraction. A Tenascin‐C targeting aptamer (GBI‐10) is modified onto (DGL‐ZA)n NPs for a tumor‐homing effect. Apt@(DGL‐ZA)n NPs show both enhanced penetration in in vitro 3D triple negative breast cancer spheroids and in vivo tumor tissues. Effective macrophage regulation, enhanced tumor autophagy, and excellent in vivo antitumor efficacy are achieved, suggesting this tactic as a significant antitumor strategy. [ABSTRACT FROM AUTHOR]

Anticancer therapies, which can induce cell death and elevate antitumor immune response in the meantime, are considered as effective treatments for many types of cancers. Immunogenic cell death (ICD) induced by chemodrugs is a promising and typical strategy to achieve cell cytotoxicity and immunological enhancement together. However, due to the low level of ICD induction and less tumor‐targeting accumulation, application of traditional ICD inducers is limited. Here, tumor‐targeting core–shell magnetic nanoparticles (ETP‐PtFeNP:α‐enolase targeting peptide modified Pt‐prodrug loaded Fe3O4 nanoparticles) are developed to reinforce ICD induction of loaded‐oxaliplatin (IV) prodrug. After tumor‐targeting accumulation and endocytosis, platinum (IV) complexes are activated by intracellular reductive elimination to yield and release the Pt (II) congener, oxaliplatin, leading to DNA lesions and reactive oxygen species (ROS) generation. Simultaneously, in‐progress‐released ferric ions elicit highly toxic ROS (·OH or ·OOH) burst and interfere with the intracytoplasmic redox balance (like endoplasmic reticulum stress), leading to ICD‐associated immunogenicity enhancement and specific antitumor immune responses to kill the tumor cells synergistically. Meanwhile, the transverse relaxation rate R2 of ETP‐PtFeNP is remarkably increased by more than three times while triggered by reductant, suggesting ETP‐PtFeNP a high‐sensitivity T2 contrast agent for magnetic resonance imaging. A tumor‐targeting core–shell magnetic nanoparticle is designed to enhance the immunogenic cell death (ICD) induction of loaded‐oxaliplatin (IV) prodrug. Oxaliplatin‐based reactive oxygen species (ROS) generation and ferroptosis‐based ROS burst coherently reinforce the immunogenic characteristics of ICD, and lead to upregulation of antitumor immune response and downregulation of PD‐L2 mediated immunosuppression, eventually killing the tumor synergistically. [ABSTRACT FROM AUTHOR]

Current strategies for Alzheimer's disease (AD) treatments focus on pathologies in the late stage of the disease progression. Poor clinical outcomes are displayed due to the irreversible damages caused by early microglia abnormality which triggers disease development before identical symptoms emerge. Based on the crosstalk between microglia and brain microenvironment, a reactive oxygen species (ROS)‐responsive polymeric micelle system (Ab‐PEG‐LysB/curcumin (APLB/CUR)) is reported to normalize the oxidative and inflammatory microenvironment and reeducate microglia from an early phase of AD. Through an β‐amyloid (Aβ) transportation‐mimicked pathway, the micelles can accumulate into the diseased regions and exert synergistic effects of polymer‐based ROS scavenging and cargo‐based Aβ inhibition upon microenvironment stimuli. This multitarget strategy exhibits gradual correction of the brain microenvironment, efficient neuroprotection, and microglia modulation, leading to decreased Aβ plaque burdens and consequently enhanced cognitive functions in APPswe/PSEN1dE9 model mice. The results indicate that microglia can be exploited as an early target for AD treatment and their states can be controlled via microenvironment modulation. A dual‐functional polymeric micelle system is designed to normalize the oxidative and inflammatory microenvironment and reeducate microglia from an early phase of Alzheimer's disease. Polymer‐based reactive oxygen species scavenging and cargo‐based β‐amyloid (Aβ) inhibition in response to the brain microenvironment can synergistically exert efficient neuroprotection and microglia modulation and lead to decreased Aβ plaque burdens and enhanced cognitive functions. [ABSTRACT FROM AUTHOR]

An Alzheimer's disease (AD) brain is featured with the oxidative and inflammatory microenvironment caused by overactivated microglia. In article number 1801586, Chen Jiang and co‐workers design a brain normalizing system to eliminate reactive oxygen species (ROS) and reeducate microglia from an early phase of AD. Through its efficient neuroprotection and microglia modulatory functions, decreased Aβ plaque burdens and improved cognition are achieved. [ABSTRACT FROM AUTHOR]