ADVANCED FUNCTIONAL MATERIALS
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2025
·
IF 19
Haoting Chen,Ding Yang,Dongyue He,Zechuan Li,Gengyou Li,Jing Ma,Jiaqing Wan,Meifen Luo,Qi Chen,Yansong Liu,Qihan Zhang,Yanwen Liang,Ying-Shi Sun,Weisheng Guo,Lu Liu
Immune checkpoint blockade (ICB) therapies have transformed the management of metastatic and advanced malignancies. A novel therapeutic paradigm targeting CD47 has emerged as a promising approach to enhance macrophage-mediated tumor phagocytosis; however, systemic toxicity stemming from nonspecific antibody distribution remains a critical clinical challenge. To address this limitation, a modular nanoparticle system, termed Differentiation Responsive Architected Macrophage (DREAM), was engineered to exploit intrinsic macrophage homing for tumor-specific co-delivery of anti-CD47 antibodies (aCD47) and Resiquimod (R848). This platform circumvents reliance on tumor microenvironment-derived matrix metalloproteinase-9 (MMP-9) by utilizing autocrine MMP-9 secretion to initiate spatially controlled drug release, while simultaneously amplifying protease production via dynamic macrophage differentiation. In vitro analyses demonstrated stimulus-responsive payload dissociation kinetics. In vivo evaluation in murine tumor models revealed that systemic DREAM administration induced robust tumor regression following three treatment cycles, concomitant with a shift in immune microenvironment polarization from an immunosuppressive to pro-inflammatory phenotype. By integrating autonomous activation mechanisms with cell-specific targeting, this strategy establishes a macrophage-centric delivery platform that enhances therapeutic precision, mitigates off-tissue toxicity, and augments antitumor efficacy, thereby advancing the translational potential of next-generation ICB modalities.
研究领域:
肿瘤学
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免疫学
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纳米医学
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产品关联
DOI
高影响因子
ACS Applied Materials & Interfaces
·
2024
·
IF 8.3
Cai Zhang,Zheng Deng,Xianglong Sun,Kangzhi Yuan,Jiadong Wang,Xirui Wu,Yifan Zhang,Kai Yang,Junjun Zhang,Guangbao Yang
The morphological features of materials significantly influence their interactions with cells, consequently affecting the cellular uptake of these materials. In this study, we examine the cellular uptake behavior of spherical metal–organic frameworks (MOFs) and petaloid MOFs, both possessing similar sizes and compositions. In comparison to spherical MOFs, dendritic cells (DCs) and macrophages exhibit superior phagocytic uptake of petaloid MOFs. Next, the results demonstrate that R848@petaloid MOFs more effectively promote the repolarization of tumor-associated macrophages (TAMs) from the M2 to M1 phenotype and the maturation of DCs. More importantly, the R848-loaded petaloid MOFs are found to significantly enhance the therapeutic effects of radiotherapy (RT) by eliciting antitumor responses. Furthermore, R848@petaloid MOFs combined with RT and αPD-L1 elicit a potent abscopal effect, effectively suppressing tumor metastasis. Therefore, this work proposes a new strategy to enhance the uptake of immunomodulators by immune cells through modulating the morphology of drug delivery carriers.
研究领域:
生物材料学
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免疫学
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肿瘤学
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产品关联
DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2024
·
IF 10
Mengna Sun,Tianyu Shi,Subiyinuer Tuerhong,Mengru Li,Qiaoli Wang,Changchang Lu,Lu Zou,Qinghua Zheng,Yingxin Wang,Juan Du,Rutian Li,Baorui Liu,Fanyan Meng
In situ vaccination is an attractive type of cancer immunotherapy, and methods of persistently dispersing immune agonists throughout the entire tumor are crucial for maximizing their therapeutic efficacy. Based on the probiotics usually used for dietary supplements, an immunomodulator-boosted Lactococcus lactis (IBL) strategy is developed to enhance the effectiveness of in situ vaccination with the immunomodulators. The intratumoral delivery of OX40 agonist and resiquimod-modified Lactococcus lactis (OR@Lac) facilitates local retention and persistent dispersion of immunomodulators, and dramatically modulates the key components of anti-tumor immune response. This novel vaccine activated dendritic cells and cytotoxic T lymphocytes in the tumor and tumor-draining lymph nodes, and ultimately significantly inhibited tumor growth and prolonged the survival rate of tumor-bearing mice. The combination of OR@Lac and ibrutinib, a myeloid-derived suppressor cell inhibitor, significantly alleviated or even completely inhibited tumor growth in tumor-bearing mice. In conclusion, IBL is a promising in situ tumor vaccine approach for clinical application and provides an inspiration for the delivery of other drugs.
研究领域:
肿瘤学
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免疫学
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微生物学
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产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2024
·
IF 8.3
Jia-Xian Li,Na Shu,Yao-Jun Zhang,Qi-Song Tong,Ling Wang,Jing-Yang Zhang,Jin-Zhi Du
Tumor-associated macrophages (TAMs) usually adopt a tumor-promoting M2-like phenotype, which largely impedes the immune response and therapeutic efficacy of solid tumors. Repolarizing TAMs from M2 to the antitumor M1 phenotype is crucial for reshaping the tumor immunosuppressive microenvironment (TIME). Herein, we developed self-assembled nanoparticles from the polymeric prodrug of resiquimod (R848) to reprogram the TIME for robust cancer immunotherapy. The polymeric prodrug was constructed by conjugating the R848 derivative to terminal amino groups of the linear dendritic polymer composed of linear poly(ethylene glycol) and lysine dendrimer. The amphiphilic prodrug self-assembled into nanoparticles (PLRS) of around 35 nm with a spherical morphology. PLRS nanoparticles could be internalized by antigen-presenting cells (APCs) in vitro and thus efficiently repolarized macrophages from M2 to M1 and facilitated the maturation of APCs. In addition, PLRS significantly inhibited tumor growth in the 4T1 orthotopic breast cancer model with much lower systemic side effects. Mechanistic studies suggested that PLRS significantly stimulated the TIME by repolarizing TAMs into the M1 phenotype and increased the infiltration of cytotoxic T cells into the tumor. This study provides an effective polymeric prodrug-based strategy to improve the therapeutic efficacy of R848 in cancer immunotherapy.
研究领域:
药理学
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免疫学
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纳米技术
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肿瘤学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
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2024
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IF 10.5
Xinyi Li,Yuyi Qian,Xin Lu,Mingzhen Xu,Simin He,Jianping Zhang,Shaoli Song
Transarterial radioembolization (TARE) is a recommended locoregional strategy for intermediate hepatocellular carcinoma (HCC), whereas, the effect is insufficient to reverse the immunosuppression tumor microenvironment, and the overall benefits for patients remain to be improved. In this study, a multifunctional microsphere (MS) 131 I-ICT/R848-MS is developed to propose an approach combined with TARE, icaritin (ICT) and immune modulator resiquimod (R848). ICT and iodine-131 ( 131 I) radiation can induce immunogenic cell death, which, in combination with R848, will boost dendritic cell (DC) maturation. Decellularized liver model and SPECT/CT imaging revealed high specificity and long retention of microspheres. Radioactive distribution of 131 I in tumor on 7 d following 131 I-MS injection was over 7 times of that in normal liver tissue (4.26 ± 1.21 % ID/g vs 0.57 ± 0.23 % ID/g). 131 I-ICT/R848-MS embolization brought significant immune activation, where the ratio of cytotoxic T lymphocytes to regulatory T cells in tumor sites upregulated from 1.75 ± 0.20 to 24.31 ± 1.79, and DC maturation in lymph nodes increased from 8.90 ± 1.51 % to 34.70 ± 3.12 %. Enhanced anti-tumor efficacy with no relapse was proved in rat orthotopic N1S1 HCC models. These results demonstrated the great potential of this multifunctional embolic agent to treat HCC through transarterial radio-immuno-chemoembolization (TARICE).
研究领域:
肿瘤学
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放射肿瘤学
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免疫疗法
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医学影像
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药理学
✓ 已验证
DOI
PubMed
高影响因子
Acta Biomaterialia
·
2026
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IF 10.4
Wenfeng Zeng,Juntao Xie,Yeqi Shen,Yiqiu Fu,Xinyi Wang,Wen Li,Qingyun Liu,Hanyue Li,Jiahui Cao,Yongkang Yu,Jisheng Xiao,Meitong Ou,Lin Mei
Immune suppression of tumor microenvironment (TME) limits the effectiveness of the immune therapy. Although inducing tumor cell pyroptosis and activating innate immunity are effective strategies to reverse this microenvironment, current methods are often hindered by non-targeted toxicity and the inability to precisely control drug release. To address these challenges, we synthesized an ROS-responsive R848 prodrug with a maleimide structure. Then, Hemin was coupled to bovine serum albumin (BSA) and the disulfide bonds within the BSA molecule were reduced, exposing free thiol groups. The R848 prodrug was then conjugated to the thiol groups, and the photosensitizer Ce6 was loaded, allowing self-assembly into the HBSA@CR nanoagonist. This strategy not only achieved a higher drug loading capacity than traditional albumin nanoparticles, but also retained the biocompatibility of natural albumin and the advantages of receptor-mediated cellular uptake. HBSA@CR can be activated by 660 nm laser irradiation to efficiently generate ROS through photodynamic and enzymatic catalysis. In vitro experiments show that this nanoparticle can efficiently kill tumor cells, induce pyroptosis through the Caspase-3/GSDME pathway and trigger the release of R848. In tumor-bearing mouse models, HBSA@CR effectively inhibited primary tumor growth and lung metastasis, and reprogrammed the immunosuppressive TME. In a tumor rechallenge model, this strategy prevented tumor recurrence and conferred long-lasting immunological memory. Moreover, when used in combination with the immune checkpoint inhibitor αPD-L1, this nanoparticle exhibits synergistic therapeutic effects. The designed nanoagonist offers a biomimetic platform for combined photo-immunotherapy, which achieves controlled R848 release while inducing tumor cell pyroptosis, reprogramming the immunosuppressive TME, and eliciting durable antitumor immunological memory. Statement of Significance The immunosuppressive tumor microenvironment is one of the main obstacles to effective immunotherapy, severely restricting the clinical efficacy. Inducing pyroptosis and stimulating innate immune activation are effective strategies for reprogramming the tumor microenvironment, but existing methods often face problems such as the lack of selectivity in inducing pyroptosis and the high toxicity of systemic administration of immune agonists. In this study, a nanoagonist HBSA@CR was constructed, which retains the biocompatibility and receptor-mediated tumor uptake of native albumin. This nanoplatform utilizes ROS to induce tumor cell pyroptosis and drive the controlled release of R848, achieving precise local pyroptosis induction and innate immune activation, effectively reprogramming the immunosuppressive microenvironment and stimulating persistent anti-tumor immune memory. Download: Download high-res image (309KB) Download: Download full-size image
✓ 已验证
DOI
高影响因子
Theranostics
·
2025
·Vol. 15
·期 16
·8096
·
IF 13.3
Zhen Wang,Xiaolei Lu,Lingzhi Wu,Xin Jiang,Wei Wang,Yahua Wang
Rationale: The cutaneous route exploits the immunocompetence of the skin, making it a favourable route for allergen-specific immunotherapy (AIT), but there must be a balance between minimal skin disruption and precise allergen delivery. Thus, we propose the use of powder-laden microneedles (pMNs) for the sustained epidermal delivery of powdery hypoallergens and immunomodulators. Methods: In this study, targeted hypoallergenic derivatives, namely, mannan-ovalbumin (mOVA) conjugates, were synthesized in a single-step process. For minimally invasive self-administration into the skin, pMNs were constructed using highly biocompatible silk fibroin (SF) with a cavity in the basal portion of each needle, which was filled with lyophilized mOVA and resiquimod powders (mOVA/R848 pMN). The resulting mOVA/R848 pMN arrays were thoroughly examined for their physical morphology, mechanical property, accumulation ability, and immune profile. Results: The deposition of powdery mOVA and R848 improved uptake by skin dendritic cells (DCs) and stimulated the immune system more than 10 d after application. On the basis of these features, mOVA/R848 pMN arrays increased the induction of protective immune mechanisms to suppress Th2 immunity, including the Treg/Th1 bias, as well as the production of anti-inflammatory cytokines and neutralizing antibodies in an asthmatic mouse model. Compared with traditional subcutaneous immunotherapy (SCIT), a total dose of only 75 μg of OVA over three treatments was sufficient to restore immune balance and alleviate allergic symptoms during allergen exposure, highlighting the dose-sparing and frequency-sparing potential of mOVA/R848 pMN. Conclusion: Optimal mOVA/R848 pMN arrays represent a new therapeutic strategy for allergy treatment with convenient administration and satisfactory outcomes.
研究领域:
生物医学工程
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免疫学
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药学
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材料科学
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产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2024
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IF 13.3
Xinmin Zheng,Xiang Li,Guolin Shi,Yidan Zhou,Jinxiao Yan,Hao Zhang,Xiru Liu,Jiangong Zhang,Yu Liu,Liangliang Dai,Hui Yang
The low targeting of immunity regulators & chemotherapy drugs and immune tolerance in the tumor microenvironment significantly hindered the chemo-immunotherapy effect. In this work, an MMP-2/GSH-responsive nanobomb loading Resiquimod (R848) and prodrug Cisplatin (Pt) with hierarchical drug delivery and tumor associated macrophages (TAMs) polarization traits was designed for improved chemo-immunotherapy. The Pt-carrying dendrimers penetrate the depth of tumor tissues under MMP-2 and activate the cytotoxicity of Pt prodrug in response to GSH, causing effective tumor damage and enhancing immunogenicity. Meanwhile, R848 is effectively uptake by TAMs, which were re-educated and then greatly relieved immune resistance. In vitro and in vivo results collectively revealed that the nanosystem could not only overcome the barrier of tumor penetration and the heterogeneity action sites of drugs but also re-educate TAMs and suppress immune evasion via activating extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) signal pathway regulated by heparin binding EGF like growth factor ( Hbegf ) gene. The gene silencing or knockout in vitro and in vivo demonstrated that Hbegf could regulate the re-education of TAMs and the progression of tumors.
研究领域:
肿瘤学
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免疫学
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药剂学
✓ 已验证
产品关联
DOI
高影响因子
ACS Applied Materials & Interfaces
·
2023
·
IF 9.5
Jiamin Chen,Xingxing Liu,Shujing Zhao,Hongyican Chen,Tao Lu,Jinfeng Wang,Jiahui Han,Wangran Wu,Xian Shen,Chao Li
Due to the intrinsic weak immunogenicity of tumor cells and the quantitatively and functionally different populations of immune cells, immunosuppression has become the major obstacle for cancer immunotherapy. In this study, the biocompatible alginate was chemically modified with the carboxyethyl linker to facilitate the esterification reaction of the resultant carboxymethylated alginate (CMA) and resiquimod (R848), the agonist of Toll-like receptor 7/8 (TLR7/8a). In aqueous solution, the hydrophilic CMA and the hydrophobic R848 formed stable nanomicelles (CMA-R848) by self-assembling. After combined administration of CMA-R848 and cisplatin (Cis) in a gastric cancer (GC) model, the long-circulating CMA-R848 micelle reached the mild acidic tumor microenvironment (TME); the ester bonds were quickly cleaved by the ubiquitous esterase and released the single molecule of R848. In vitro and in vivo results demonstrated that the released R848 efficiently promoted co-stimulatory molecules’ expression of dendritic cells (DCs), enhanced the antigen uptake and cross-presentation, and primed the cytotoxic T lymphocytes’ (CTLs) infiltration and killing effects, thereby reprogramming the “cold tumor” into the “hot tumor”. In addition, the ex vivo tumor sections revealed that the released R848 effectively repolarized the M2-like tumor-associated macrophages (TAMs) into M1-like macrophages, exerted synergistic antitumor activity, reduced the tumor burden, and prolonged the overall survival duration of the GC animal model. Our study provided a targeting therapeutic strategy overcoming the limitations of R848 in vivo, and enhanced the efficacy of GC chemotherapy and immunotherapy by TME modulation.
研究领域:
肿瘤学
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药学
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免疫学
·
生物技术
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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