Advanced Healthcare Materials
·
2025
·
IF 9.6
Yunfeng Tang,Xiangtian Deng,Min Yi,Dong Wang,Cheng Zheng,Shichang Zhao,Renliang Zhao
Melanoma remains one of the most aggressive skin cancers with high recurrence rates following surgical resection. To overcome the challenges of residual tumor cells and postoperative immune resistance, an injectable hydrogel is developed that co-delivers propranolol (Pro) and imiquimod (IMQ). The rationale is to achieve a synergistic therapeutic effect by enhancing immunogenic cell death (ICD) and strengthening antitumor immunity. The hydrogel is synthesized via boronate ester crosslinking between HA-EGCG and CMCS-PBA and demonstrates excellent injectability, self-healing, biodegradability, and tissue adhesion. In vitro, Pro potentiated IMQ-induced reactive oxygen species (ROS) production, enhancing ICD markers such as calreticulin exposure (CRT), high mobility group box 1 (HMGB1), and adenosine triphosphate (ATP) release, thereby promoting dendritic cell maturation and T cell activation. In vivo, Pro/IMQ@ Hydrogel (PIH) effectively inhibited tumor recurrence in an incomplete melanoma resection model, significantly reducing tumor volume and inducing apoptosis without systemic toxicity. Immunohistochemical analyses revealed increased CD8⁺ and CD4⁺ T cell infiltration, elevated inflammatory cytokine levels, and enhanced memory T cell responses. This work highlights the potential of PIH as a potent localized chemo-immunotherapy platform for melanoma by converting “cold” tumors into “hot” immunogenic lesions.
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ACS Applied Nano Materials
·
2026
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IF 5.8
Yanping Chen,Baoru Fang,Ke Wang,Siqi Geng,Fang Wang,Lin Xu,Zhiqiu Ye,Fei Xu,Zhangsen Yu
Radiofrequency ablation (RFA), a widely used minimally invasive therapy for primary liver cancer, induces tumor cell necrosis and immunogenic cell death, thereby activating antitumor immunity. However, its efficacy is often compromised by incomplete ablation of marginal regions and insufficiently robust immune activation, leading to a high risk of post-treatment recurrence and metastasis. Currently, integrating RFA with multifunctional nanomedicines is a promising strategy to overcome these limitations. Herein, we developed a multifunctional, targeted thermosensitive ultrasound contrast agent, termed TUCA(R837)-SP94, for synergistic RFA/immunotherapy against hepatocellular carcinoma (HCC). TUCA(R837)-SP94 integrates three major innovations: (1) tumor-targeting via the SP94 peptide enables enrichment at tumor sites; (2) under the thermal effects of RFA, the loaded perfluoropentane (PFP) undergoes a liquid–gas phase transition, enhancing the ultrasound contrast imaging effect; (3) RFA thermal effects trigger liposome release of imiquimod (R837). This study prepared TUCA(R837)-SP94 via the thin-film hydration method and characterized it, evaluated its ultrasound imaging performance and in vitro immune responses, and systematically investigated the synergistic therapeutic effects and immunomodulatory mechanisms of TUCA(R837)-SP94 combined with RFA through the establishment of mouse models of in situ and metastatic hepatocellular carcinoma. Results indicate that TUCA(R837)-SP94 combined with RFA significantly inhibits tumor growth both in situ and distally. This approach promotes DC maturation, increases the ratio of cytotoxic T cells to helper T cells in the tumor region, and reduces the proportion of regulatory T cells, while demonstrating excellent biosafety. Collectively, TUCA(R837)-SP94-based RFA/immunotherapy synergistic treatment represents a safe and effective theranostic platform for hepatocellular carcinoma, demonstrating promising potential for clinical translation and application.
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ACS Applied Materials & Interfaces
·
2022
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IF 10.383
Meiting Li,Yaqian Zhang,Xiaoge Zhang,Zhuoyin Liu,Junjie Tang,Miao Feng,Baizhu Chen,Dalin Wu,Jie Liu
Sonodynamic therapy (SDT) benefiting from its intrinsic merits, such as noninvasiveness and deep tissue penetrability, is receiving increasing considerable attention in reactive oxygen species (ROS)-based tumor treatment. However, current sonosensitizers usually suffer from low tumor lesion accumulation, insufficient ROS generation efficiency under ultrasound, and non-biodegradability, which seriously impede the therapeutic outcomes. Additionally, it is difficult that SDT alone can completely eradicate tumors because of the complex and immunosuppressive tumor microenvironment (TME). Herein, we simultaneously employ sonosensitive porphyrin building blocks and glutathione (GSH)-responsive disulfide bonds to construct a novel degradable multifunctional porphyrin-based hollow porous organic polymer (POP) nanosonosensitizer (H-Pys-HA@M/R), which combine SDT, “on-demand” chemotherapy, and immunotherapy. Taking the unique advantages of POPs with designable structures and high specific surface area, this H-Pys-HA@M/R nanosonosensitizer can achieve tumor target accumulation, GSH-triggered drug release, and low-frequency ultrasound-activating ROS generation with encouraging results. Furthermore, this multifunctional nanosonosensitizer can effectively evoke immunogenic cell death (ICD) response through the combination of SDT and chemotherapy for both primary and distal tumor growth suppression. Meanwhile, H-Pys-HA@M/R exhibits favorable biodegradation and biosafety. Therefore, this study provides a new strategy for reasonably designing and constructing POP-related sonosensitizers combining SDT/chemotherapy/immunotherapy triple treatment modalities to eradicate malignant tumors.
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JOURNAL OF CONTROLLED RELEASE
·
2022
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IF 11.467
Hong Liu,Zhenfu Wen,Haolin Chen,Zeyu Yang,Zhicheng Le,Zhijia Liu,Yongming Chen,Lixin Liu
Great efforts have been made to manipulate nanoparticles (NPs) with a diameter of 10–100 nm to passively target lymph nodes (LNs) to magnitude anti-tumor activity of T cells . However, no attention has been paid to increasing the retention of NPs with active affinity in order to induce a prolonged release of antigens or molecular adjuvants in the LNs mattering the immune response. Here, we formulated two NPs encapsulated with imiquimod (IMQ), a TLR7/8 agonist, and paclitaxel (PTX) and further modified them with tannic acid (TA), respectively, to generate IMQ NP and PTX NP with a final diameter of approximately 40 nm. Attributing a strong affinity of TA molecules to the elastin of LN conduits, the TA modified IMQ NPs can bypass the gaps in the layer of lymphatic endothelial cells and enter the paracortex through the lymph node capsule-associated (LNC) conduits. Similarly, the TA modified PTX NPs increased delivery of PTX to the metastatic tumor site in LNs, where the tumor-associated antigens were released and presented by conduits-lining dendritic cells to activate T cells. Thus, the NPs with deposition to LN conduits showed excellent performance in preventing lymphovascular invasion of triple-negative breast cancer cells and lung metastasis thereafter. On the contrary, the NPs without TA flowed through the subcutaneous sinus existing LNs directly by efferent lymphatic vessels showing relatively poor therapeutic outcomes. This study reveals that TA may mediate the long retention of antigens and molecular adjuvants to be delivered to deep LNs for developing potent vaccination technology.
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Cancer Nanotechnology
·
2023
·Vol. 14
·期 1
·1-18
·
IF 5.7
Lu Dehua,Xu Yanming,Yang Xiaodong,Li Ying,Li Mengqing,Zheng Yuanyuan,Wang Yuenan,Wang Weihu,Wang Shubin,Gao Jing,Liu Yajie
Background Increasing evidence indicates that radiotherapy (RT) has synergistic inhibitory efficiency with immunotherapy agents in multiple cancers and enhances abscopal effects by regulating the innate immune response, which was further investigated in this study. Neutrophils are recruited in radiated tumors. Therefore, neutrophil membrane-coated nanoparticles potentially deliver R837 (Toll-like receptor 7 agonist) to radiated tumors.Methods A novel nanoparticle R837@PLGA@Neu was prepared by initially assembling PLGA (poly (lactic-co-glycolic acid)) with R837 (TLR7 agonist) into R837@PLGA followed by coating with neutrophil membrane. Characterizations of R837@PLGA@Neu were performed. Tumor targeting efficiency was evaluated by in vivo fluorescent imaging of CT26-bearing mice. Treatments of R837@PLGA@Neu combined with RT were carried out in unilateral and bilateral CRC tumor-bearing mice, followed by validations of immune cells in tumors by flow cytometry.Results The characteristics of R837@PLGA@Neu were well identified, and it was confirmed to have high uptake ability and low cytotoxicity in colorectal cancer (CRC) cells in vitro, as well as its strong tumor-targeting efficiency in vivo in CRC tumor-bearing mice. The exciting findings were that R837@PLGA@Neu combined with RT exerted prominent tumor inhibition not only in radiated tumors, but also in distant tumors without RT, suggesting its enhancement of the efficacy and abscopal effect of RT. The possible underlying mechanisms were remodeling of the tumor microenvironment by triggering mature dendritic cells and CD8+ T cells.Conclusion In summary, our findings suggested that neutrophil membrane-derived nanoparticle R837@PLGA@Neu with high uptake ability and low cytotoxicity showed strong tumor-targeting efficiency, and combination with RT had a promising effect in CT26-bearing mice via immune cell regulation. Our results provide a probable combination strategy for CRC treatment.
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CHEMISTRY OF MATERIALS
·
2021
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IF 9.811
Jiexin Li,He Ren,Yaping Sun,Gengqi Liu,Xingyue Yang,Qian Qiu,Yuanmeng Ding,Jonathan F. Lovell,Yumiao Zhang
Cancer peptide vaccines face challenges for antigen delivery and presentation. In the present work, we develop a self-assembled magnetic micelle delivery system for CD8+ T-cell epitopes that produces strong cellular immune responses. Hydrophobically modified imiquimod R837 and Zn1.15Fe1.85O4 are coencapsulated in the core of Pluronic F127 block copolymer micelles. Magnetic Zn1.15Fe1.85O4 enables externally targeted delivery and enrichment of micelles in lymph nodes. Furthermore, metal ions are found to enhance vaccine immunogenicity. F127 micelles were chemically modified by a self-immolative linker so that antigens are rapidly and reversibly grafted on micelles in an aqueous solution. With the assistance of an external magnetic field, once the magnetic micelles are delivered to lymph nodes and taken up by immune cells, intracellular glutathione cleaves the disulfide bond and releases pristine short peptide antigen. Delivery to lymph nodes is tracked by magnetic resonance and fluorescence imaging. The use of this vaccine system eradicated tumors in a murine tumor model. Thus, integrating multiple functionalities in a single micellar delivery system, including responsive linkage, multiple immunostimulatory molecules, targeted delivery, and bimodal imaging, demonstrates the potential for theranostic approaches to develop a new generation of cancer vaccines.
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MOLECULAR PHARMACEUTICS
·
2023
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IF 4.9
Haifeng Ni,Sunxiang Qian,Jie Lu,Jie Feng,Xiao-zhou Mou,Jing Zhang
Chemoimmunotherapy is an effective cancer treatment method. Drugs are always combined and used in treating cancer. However, the characteristic of drugs varies, making it challenging to control their release kinetics utilizing delivery devices with a single microstructure. In this study, we attempted to uniformly size drugs of varying molecular weights and confine them in a compartment where immune cells may be recruited and moved freely. Dextran microgels were created as modular drug libraries to address the cryogel burst release of small molecule drugs. Then, modular drug libraries and granulocyte-macrophage colony-stimulating factor (GM-CSF) were integrated into cryogels for a combined treatment. Herein, alginate was zwitterion modified to avoid the immune reaction generated by the material. Because of its macroporous structure, the cryogel could be injected into the body, eliminating invasive surgical procedures. Results demonstrated that multiscale delivery platforms could improve the synergistic effect of various medications on tumor treatment.
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JOURNAL OF NANOBIOTECHNOLOGY
·
2021
·Vol. 19
·期 1
·1-16
·
IF 10.435
Zhang Lirong,Zhang Jingjing,Xu Lixia,Zhuang Zijian,Liu Jingjin,Liu Suwan,Wu Yunchao,Gong Aihua,Zhang Miaomiao,Du Fengyi
Background Therapeutic tumor vaccine (TTV) that induces tumor-specific immunity has enormous potentials in tumor treatment, but high heterogeneity and poor immunogenicity of tumor seriously impair its clinical efficacy. Herein, a novel NIR responsive tumor vaccine in situ (HA-PDA@IQ/DOX HG) was prepared by integrating hyaluronic acid functionalized polydopamine nanoparticles (HA-PDA NPs) with immune adjuvants (Imiquimod, IQ) and doxorubicin (DOX) into thermal-sensitive hydrogel. Results HA-PDA@IQ NPs with high photothermal conversion efficiency (41.2%) and T 1 -relaxation efficiency were using HA as stabilizer by the one-pot oxidative polymerization. Then, HA-PDA@IQ loaded DOX via π-π stacking and mixed with thermal-sensitive hydrogel to form the HA-PDA@IQ/DOX HG. The hydrogel-confined delivery mode endowed HA-PDA@IQ/DOX NPs with multiple photothermal ablation performance once injection upon NIR irradiation due to the prolonged retention in tumor site. More importantly, this mode enabled HA-PDA@IQ/DOX NPs to promote the DC maturation, memory T cells in lymphatic node as well as cytotoxic T lymphocytes in spleen. Conclusion Taken together, the HA-PDA@IQ/DOX HG could be served as a theranostic tumor vaccine for complete photothermal ablation to trigger robust antitumor immune responses.
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CHEMICAL ENGINEERING JOURNAL
·
2021
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IF 13.273
Yuting Cao,Yan Zhou,Jinbin Pan,Xinyu Zhong,Jianmin Ding,Xiang Jing,Shao-Kai Sun
The minimal invasive percutaneous microwave ablation (MWA) combined with immunotherapy is a promising technique in clinic for the treatment of primary and metastatic tumors. However, elaborate encapsulation carrier designs, complex cellular engineering, and poor applicability are the vexing problems difficult to solve currently. Herein, a general strategy was proposed for the design of an injectable microwave-sensitive immune hydrogel for combined MWA and immunotherapy in vivo for the first time. The mix-and-use hydrogel composed Food and Drug Administration (FDA)-approved components were fabricated by introducing various immunostimulants regardless of hydrophilicity and hydrophobicity into the alginate (ALG)-Ca 2+ hydrogel. As a proof of concept, an immunoadjuvant (R837) was employed to synthesize the R837-ALG-hydrogel for systematic studies. This immune hydrogel owns ultra-facile synthesis process, good microwave-sensitivity, adjuvant encapsulation efficiency of nearly 100%, good biocompatibility and syringeability, and large-scale production capability, which could be easily injected into the primary tumor for enhancing MWA. Moreover, the loaded R837 could motivate in situ vaccination by making the utmost of the tumor-associated antigens released after MWA, thereby inducing the robust tumor-specific antitumor immunity to suppress the distant metastatic tumor in vivo. The proposed injectable microwave-sensitive immune hydrogel paves a facile but general avenue with great clinical translation potential for the minimal invasive personalized oncotherapy.
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JOURNAL OF APPLIED TOXICOLOGY
·
2020
·Vol. 41
·期 5
·724-735
·
IF 2.997
Zhaocheng Li,Jiyuan Gao,Zexing Xiang,Honglei Zhang,Yibei Wang,Xuefei Zhang
Cancer immunotherapy is a promising method for cancer therapy. Imiquimod (R837) is a molecule that could activate immune systems for cancer immunotherapy, but an easily manufactured biocompatible carrier to deliver R837 may be needed to overcome the disadvantages of R837. Micelles formed by biocompatible copolymers have been widely used to deliver chemotherapeutic drugs but not immunotherapeutic drugs. In this study, R837 was linked to an amphiphilic biodegradable copolymer mPEG-b-PLA via acid-sensitive Schiff bases. The molecular structures were investigated by 1 H nuclear magnetic resonance, gel permeation chromatography and Fourier transform infrared spectroscopy. The product could be self-assembled into micelles with R837 content as high as 22.4%. Owing to acid-cleavable Schiff bases, the release of R837 from micelles was markedly accelerated under acidic media. Consequently, the micelles linked with R837 stimulated the expression of major histocompatibility complex II-stimulating molecules on the surface of RAW 264.7 macrophages at pH 6.5 but not pH 7.4. By using human umbilical vein endothelial cells as the in vitro model, it was shown that the polymer carriers and R837-linked micelles were minimally cytotoxic and did not induce the activation of endothelial cells under physiological pH, which suggested the relatively high biocompatibility. In conclusion, this study successfully developed pH-responsive immunotherapeutic drug-loaded micelles that could activate macrophages at acidic pH in vitro. The high biocompatibility of the micelles to endothelial cells also indicated the potential uses under in vivo conditions.
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BIOMATERIALS
·
2020
·
IF 10.317
Fan Jiang,Binbin Ding,Shuang Liang,Yajie Zhao,Ziyong Cheng,Bengang Xing,Ping'an Ma,Jun Lin
Rational design of biocompatible nanoplatforms simultaneously realizing multimodal imaging and therapeutic functions is meaningful to cancer treatment. Herein, the MoS 2 –CuO heteronanocomposites are designed by integrating semiconductor CuO and flower-like MoS 2 via a two-step hydrothermal method . After loading bovine serum albumin (BSA) and immunoadjuvant imiquimod (R837), the obtained MoS 2 –CuO@BSA/R837 (MCBR) nanoplatforms realize the excellent computed tomography/infrared thermal/magnetic resonance multi-mode bioimaging as well as significantly enhanced antitumor efficacy of synergetic photothermal therapy (PTT)/chemodynamic therapy (CDT)/immunotherapy. In this nanoplatform, the semiconductor CuO exhibits peroxidase-like activity, which can react with over-expressed H 2 O 2 in tumor microenvironment (TME) to generate OH for CDT via Haber-Weiss and Fenton-like reactions. And this process can be further accelerated by the generated heat of MoS 2 under 808 nm laser irradiation . More importantly, the obtained multifunctional MCBR nanoplatforms under near-infrared (NIR) irradiation would destroy tumor cells to generate tumor associated antigens (TAAs), which combine with R837 as an adjuvant to trigger strong antitumor immune responses for effectively eliminating primary tumors and metastatic tumors.
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BIOMATERIALS
·
2021
·
IF 12.479
Lili Cheng,Xiaoge Zhang,Junjie Tang,Qijun Lv,Jie Liu
CD47 , overexpressed on kinds of tumor cells, activates a “don't eat me” signal through binding to signal regulatory protein α (SIRPα), leading to immune escape from the mononuclear phagocyte system (MPS). It is also a huge challenge to deliver therapeutic drugs to the tumor sites due to the short retention time in blood, poor targeting of tumor cells and accelerated clearance by MPS. Herein, we designed a hybrid therapeutic nanovesicles, named as hGLV, by fusing gene-engineered exosomes with drug-loaded thermosensitive liposomes . We demonstrated that the CD47-overexpressed hGLV exhibited the long blood circulation and improved the macrophages-mediated the phagocytosis of tumor cells by blocking CD47 signal. Moreover, the resulted hGLV could remarkably target the homologous tumor in mice, achieving the preferential accumulation at the tumor sites. Importantly, hGLV loading the photothermal agent could achieve the excellent photothermal therapy (PTT) under laser irradiation after the intravenous injection, completely eliminating the tumors, leading to immunogenic cell death and generating substantial tumor-associated antigens, which could promote the maturation of immature dendritic cells with the help of the co-encapsulated immune adjuvant to trigger strong immune responses. Generally, the hybrid nanovesicles based on CD47 immune check point blockade can be a promising platform for the drug delivery in cancer treatment.
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