Advanced Healthcare Materials
·
2025
·
IF 9.6
Chenglong Li,Shuhao Xu,Xin Li,Huaiyu Su,Can Qian,Yingying Hou,Sanjun Shi
Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by joint inflammation, damage, and disability. Activated fibroblast-like synoviocytes (FLSs), abundant in RA synovium, crucially facilitate disease progression. These activated FLSs drive RA pathogenesis by upregulating adhesion molecules, proinflammatory cytokines, chemokines, and major histocompatibility complex class II (MHC-II). This upregulation facilitates their interaction with CD4 + T cells, triggering an inflammatory cascade that exacerbates synovial inflammation. To address this, a DSPE-mPEG 2000 -GPA-KLVFF-decorated liposome loaded with dexamethasone (DPGK@Lipo-Dex) is developed to precisely target FLSs in arthritic joints. DPGK@Lipo-Dex achieves efficient binding to FLSs through a specific enzymatic interaction between fibroblast activation protein-α (FAP-α) and GPA, along with prolonged retention in the joints due to the fibrillar transformation of KLVFF. In vitro studies demonstrate that DPGK@Lipo-Dex enhances cellular uptake and reduces MHC-II expression on aggressive FLSs. In adjuvant-induced arthritis (AIA) rats, DPGK@Lipo shows specific distribution patterns that target both inflamed joints and FLSs. Treatment with DPGK@Lipo-Dex leads to a downregulation of MHC-II expression, a decrease in the number of activated T cells within the synovium, and a reduction in levels of proinflammatory mediators. Overall, DPGK@Lipo-Dex effectively suppresses FLSs-related responses and ultimately results in inflammatory remission. This makes DPGK@Lipo-Dex a promising candidate for nano-therapeutic treatment in rheumatoid arthritis.
研究领域:
免疫学
·
纳米医学
·
风湿病学
·
分子靶向治疗
·
药剂学
·
转化医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2026
·
IF 7.8
Li Xiang,Jiachi Xu,Yukang Lin,Xianjing Xiang,Qiangqiang Jiao,Sainan Zhu,Wenhui Zhang,Yuting Qin,Yuping Chen
Fibrotic tumor microenvironment driven by activated hepatic stellate cells (aHSCs) and cancer-associated fibroblasts poses a formidable challenge to antitumoral drug delivery in hepatocellular carcinoma (HCC) by promoting angiogenesis, immunosuppression, and dense extracellular matrix barrier. Overcoming this fibrosis-associated delivery resistance requires nanotherapeutic systems to not only target the stromal compartment but also adapt their structure within the tumor matrix to improve deep penetration. Herein, we report a fibroblast activation protein-α (FAP-α)-responsive, size-transformable lipid nanoparticle platform with integrated stromal targeting, enzymatic activation, and intracellular delivery capacity for enhanced drug penetration and stromal remodeling in fibrotic HCC. This developed system, denoted as SOR/DOX@GPA-LNP, is co-loaded with sorafenib and doxorubicin and engineered with three key features: (i) a FAP-α-cleavable GPA peptide linker for TME-specific activation, (ii) FAP-α-mediated targeting of aHSCs, and (iii) a PAMAM core-mediated proton sponge activity to facilitate endosomal escape. Physicochemical characterization demonstrates that GPA-LNPs possess uniform size distribution, high colloidal stability, pH-responsive release behavior, and favorable heme- and cyto-compatibility. In vitro studies confirmed their selective aHSC-targeting ability, while in vivo imaging showed enhanced accumulation and retention in nude mice bearing subcutaneous tumors and orthotopic tumor-bearing mice. GPA-LNPs exhibited size reduction (from 170.5 to 146.3 nm) upon exposure to FAP-α, which significantly improved transport in three-dimensional HCC/aHSC spheroid models and increased deeper intratumoral accumulation. This size-transformable property establishes a direct structure–property–function relationship linking FAP-α enzymatic responsiveness with enhanced stromal penetration. Functionally, SOR/DOX@GPA-LNPs simultaneously suppressed aHSC activation, disrupted the fibrotic stromal barrier, and delivered cytotoxic agents to tumor cells. In the orthotopic HCC model, SOR/DOX@GPA-LNPs achieved superior antitumor efficacy, improved stromal remodeling and reduced systemic toxicity compared to nonresponsive counterparts. Overall, this work presents a versatile strategy that couples TME-responsive size adaptability with dual-action payloads, offering a compelling approach to navigate the complexities of fibrotic HCC therapy.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF DRUG TARGETING
·
2024
·
IF 4.3
Mingli Sui,Chaoqun Wang,Yingmei Tian,Huijuan Zhang
Phototherapy can cause autophagy while killing tumour cells, leading to tumour recurrence and metastasis. Here, we constructed a laser and enzyme dual responsive nanodrug delivery system Tf-Te@CTSL-HCQ (TT@CH) to precisely regulate autophagy in synergy with phototherapy to inhibit the proliferation and metastasis of melanoma. Firstly, transferrin (Tf) was used as a nanoreactor to synthesise phototherapy agent Tf-Te by the biological template mineralisation method. Then, the thermosensitive liposome modified with FAP-α-responsive peptide (CAP) was used as a carrier to encapsulate autophagy inhibitor hydroxychloroquine (HCQ) and Tf-Te, to obtain an intelligent TT@CH delivery system. Once arriving at the tumour site, TT@CH can be cleaved by FAP-α overexpressed on cancer-associated fibroblasts (CAFs), and release Tf-Te and HCQ. Then Tf-Te can target melanoma cells and exert PTT/PDT anti-tumour effect. What’s more, hyperpyrexia induced by PTT can further promote drugs release from TT@CH. Meanwhile, HCQ simultaneously inhibited autophagy of CAFs and melanoma cells, and down-regulated IL-6 and HMGB1 secretion, thus effectively inhibiting melanoma metastasis. Pharmacodynamic results exhibited the best anti-tumour effect of TT@CH with the highest tumour inhibition rate of 91.3%. Meanwhile, lung metastatic nodules of TT@CH treated mice reduced by 124.33 compared with that of mice in control group. Overall, TT@CH provided an effective therapy strategy for melanoma.
研究领域:
肿瘤学
·
药学
·
纳米技术
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2023
·
IF 10.8
Xinyuan Zhou,Pan Zhang,Nan Liu,Xiao Zhang,Hui Lv,Wei Xu,Meirong Huo
Pancreatic cancer (PC) carries a poor prognosis among all malignancies and poses great challenges to clinical drug accessibility due to the severely fibrotic and hypoxic tumor microenvironment (TME). Therein, cancer-associated fibroblasts (CAFs), which are extremely abundant in PC, play a key role in forming the complex PC microenvironment. Therefore, a highly efficient TME reprogramming therapeutic paradigm that can specifically inhibit CAF function is urgently needed. Herein, we successfully developed a novel CAF-tailored nanosystem (Dex-GP-DOCA, DPD) loaded with a potent anti-fibrosis flavonoid compound (Quercetin, QUE), which possesses biological responsiveness to fibroblast activation protein alpha (FAP-α), prolonged TME remodeling and enhancement of clinical chemotherapeutics. Specifically, DPD/QUE allowed for extracellular matrix (ECM) reduction, vessel normalization, hypoxia-induced drug resistance reversal, and blockade of Wnt16 paracrine in CAFs. More importantly, this chemotherapy conducive microenvironment persisted for at least 8 days following treatment with DPD/QUE. It should also be noted that the effective and prolonged microenvironment modulation induced by DPD/QUE significantly improved the chemotherapy sensitivity of Abraxane and gemcitabine, the first-line chemotherapeutic drugs for PC, with inhibition rates increasing from 37.5% and 40.0% to 87.5% and 85.2%, respectively. Overall, our CAFs-targeted nanosystem showed promising prospects for remodeling the TME and facilitating chemotherapy for refractory pancreatic cancer.
研究领域:
肿瘤学
·
药理学
·
纳米技术
·
癌症生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2020
·
IF 10.317
Jing Yan,Qinghua Wu,Ziyin Zhao,Jianhua Wu,Huan Ye,Qiujun Liang,Zhuchao Zhou,Mengying Hou,Xudong Li,Yong Liu,Lichen Yin
The anticancer performance of nanomedicine is largely impeded by insufficient intratumoral penetration. Herein, tumor microenvironment (TME)-amendatory and self-adaptive nanoclusters (NCs) capable of cancer-associated fibroblasts (CAFs) depletion and size/charge conversion were engineered to mediate light-assisted, hierarchical intratumoral penetration. Particularly, large-sized NCs (~50 nm) were prepared via self-assembly of FAP-α-targeting peptide-modified, 1 O 2 -sensitive polymers, which were further used to envelope small-sized dendrimer (~5 nm) conjugated with Ce6 and loaded with DOX (DC/D). After systemic administration, the NCs efficiently targeted CAFs and generated lethal levels of 1 O 2 upon light irradiation, which depleted CAFs and concomitantly dissociated the NCs to liberate small-sized, positively charged DC/D. Such stroma attenuation and NCs transformation collectively facilitated the delivery of DC/D into deeper regions of CAF-rich tumors, where DOX and 1 O 2 provoked synergistic anti-cancer efficacies. This study provides an effective approach to facilitate the tumor penetration of nanomedicine by concurrently and spatiotemporally reconfiguring the nano-properties and remodeling the TME.
研究领域:
纳米技术
·
癌症治疗
·
药学
·
生物医学工程
✓ 已验证
DOI
PubMed
高影响因子
Nanoscale
·
2019
·Vol. 11
·期 42
·20030-20044
·
IF 6.97
Lin Hou,Dandan Chen,Lisha Hao,Chunyu Tian,Yingshan Yan,Ling Zhu,Huijuan Zhang,Yi Zhang,Zhenzhong Zhang
Cancer-associated fibroblasts (CAFs) are important barriers for nanoparticles (NPs) to deeply penetrate into tumors and severely limit the antitumor efficacy of nanomedicines. Herein, we proposed a CAF-triggered transformable drug delivery system based on a cleavable peptide responsive to fibroblast activation protein-α (FAP-α) specifically overexpressed on the surface of CAFs. The NPs were composed of cationic poly(amidoamine) (PAMAM) dendrimers cross-linked by our designed peptide, a chemotherapeutical drug was incorporated onto PAMAM using disulfide bonds and finally, hyaluronic acid (HA) was conjugated to improve the tumor targetability as well as biocompatibility through electrostatic interactions. These NPs had an initial size of ∼200 nm and negative zeta potential favorable for stable blood circulation; however, after docking with CAFs, they dissociated into smaller NPs and exposed the relative positive surface charge to facilitate penetration and enter the tumor cells together with CAFs. An interesting finding was that this system intracellularly released different levels of drugs in these two kinds of cells, which was beneficial for the disruption of the stromal barrier and increasing the local drug accumulation. Our investigation confirmed that the constructed system could alleviate the biological barriers and hold promising therapeutic efficiency for desmoplastic solid tumors.
研究领域:
纳米技术
·
肿瘤学
·
药学
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）