Food Production Processing and Nutrition
·
2026
·Vol. 8
·期 1
·72
·
IF 6.3
Niu Ruge,Xu Zhongchi,Yang Wenli,Bao Tong,Xu Fengsheng,Zhou Wenqi,Zhang Long,Jia Qi,Wang Xiaolong,Chen Jiandong,Lin Xin
Radiotherapy is a standard treatment for thoracic malignancies, but it frequently leads to radiation‑induced heart disease (RIHD), a serious and dose‑limiting complication for which no targeted therapies are currently available. Total extracts from Abelmoschus manihot (L.) (TEA), known for their cardioprotective properties, are widely used in treating various ischemic heart diseases. Here, we identify ferroptosis driven by the NOX4/SLC7A11/GPX4 axis as a core mechanism of RIHD, with GPX4 serving as the non‑redundant downstream executor. TEA effectively modulates this axis; however, it lacks cardiac selectivity, which may compromise antitumor efficacy. To overcome this barrier, we developed, characterized, and evaluated a novel nanoplatform consisting of TEA‑loaded PLGA nanoparticles conjugated with a primary cardiomyocyte‑specific homing peptide (PCM), further integrated with low-intensity focused ultrasound (LIFU)‑triggered on‑demand release (TEA@PLGA‑PCM). This system achieves superior myocardial accumulation, effectively improves cardiac function, reverses pathological remodeling, and normalizes ferroptosis markers as well as NOX4/SLC7A11/GPX4 protein expression. In summary, we successfully constructed a novel nanoplatform that represents a promising strategy for integrated targeted delivery and synergistic therapy in RIHD management. Graphical
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CELLULAR SIGNALLING
·
2025
·
IF 3.7
YaoNan Han,XingTong Wang,DeShui Yu
Spinal cord injury (SCI) is a serious central nervous system disease. Ferroptosis is one of the major causes of spinal cord neurological loss, and targeting ferroptosis is a promising therapeutic strategy. Roflumilast has shown promising applications in the treatment of neurological diseases due to its potent anti-inflammatory and anti-oxidative stress effects. This study aimed to investigate whether roflumilast could inhibit neuronal ferroptosis to improve motor function after SCI in rats. In vitro experiments, we found that roflumilast significantly increased cell survival in an in vitro ferroptosis model, improved mitochondrial function, reduced intracellular iron, reactive oxygen species (ROS), and lipid peroxides accumulation as well as the expression of the pro-ferroptosis proteins, long-chain acyl-coenzyme A synthase 4 (ACSL4), and prostaglandin-endoperoxide synthase 2 (PTGS2), and increased the expression of ferroptosis-inhibitory protein glutathione peroxidase 4 (GPX4), and ferritin heavy chain 1 (FTH1) expression. Mechanistically, these protective effects were achieved by activating AMP-dependent protein kinase (AMPK)/nuclear factor E2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling and were attenuated when AMPK signaling was blocked. In vivo experiments, roflumilast attenuated spinal cord tissue damage, increased the number of motor neuron survivors, and improved motor function after SCI in rats. Overall, activation of AMPK/Nrf2/HO-1 signaling by roflumilast attenuated neuronal ferroptosis and improved motor function after SCI in rats.
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Materials Today Bio
·
2026
·
IF 11
Yangmengyuan Xu,Yiqing Zhang,Zijie Sun,Junfeng Gong,Qi Shen,Hao Meng,Xi Liu,Junli Chen,Yaying Hao,Zhan Xu,Kui Ma,Liqian Ma,Kailu Guo,Xiaohua Pan,Xiaobing Fu,Cuiping Zhang
Hypertrophic scars (HS) lack cell-specific therapies because pathogenic hypertrophic scar fibroblasts (HSFs) are hard to inactivate without damaging human dermal fibroblasts (HDFs). Ferroptosis has emerged as a potential antifibrotic vulnerability of activated fibroblasts, yet its translational use is constrained by off-target toxicity of small-molecule inducers. Here, we report a targeted delivery strategy based on small extracellular vesicles (sEVs) surface-decorated with a fibroblast activation protein (FAP) ligand to preferentially deliver a widely used ferroptosis inducer erastin to HSFs. We confirmed that FAP is upregulated in HSFs and HS tissue, and engineered adipose-derived mesenchymal stem cell (ADSC)-derived sEVs loaded with erastin and covalently conjugated with the FAP ligand UAMC1110 (sEVs ErF ) via EDC/NHS chemistry. sEVs ErF retained typical nanoscale characteristics and EV marker profiles and showed preferential uptake by HSFs over HDFs in vitro , which was validated by competitive blocking and FAP knockdown experiments. Functionally, sEVs ErF suppressed HSF proliferation and migration and reduced α-SMA, COL I, and COL III expression, accompanied by ferroptosis-associated signatures including lipid peroxidation, glutathione depletion, labile Fe 2+ accumulation, and mitochondrial dysfunction. For localized dermal delivery, sEVs ErF were incorporated into dissolvable microneedle patches (DMNPs) with GelMA tips and a PVA backing. In a rabbit ear HS model, sEVs ErF -DMNPs reduced scar thickness and collagen deposition and modulated ferroptosis- and fibrosis-related readouts in scar tissues. Both in vitro and in vivo rescue experiments using the ferroptosis inhibitor Ferrostatin-1 confirmed that these effects were specifically mediated by ferroptosis. Collectively, these results support FAP as an actionable targeting handle for preferential delivery to scar fibroblasts and suggest that ferroptosis-associated inactivation of HSFs can be leveraged through a microneedle-enabled, locally retained sEV formulation.
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BMC GASTROENTEROLOGY
·
2026
·Vol. 26
·期 1
·120
·
IF 3.2
Teng Xiao,Sheng Shanfeng,Pan Mingyuan,Li Yuyang,Li Zheng
Background Severe acute pancreatitis (SAP) is a critical gastrointestinal disorder associated with high mortality. Dysregulated ferroptosis, an iron-dependent form of cell death, is recognized as a pivotal mechanism driving SAP progression. Although Homoplantaginin (Homo) exhibits notable anti-inflammatory and antioxidant properties, its specific role in modulating ferroptosis during SAP remains unclear. Objective To investigate whether Homo alleviates SAP by inhibiting ferroptosis via the circDNMT3B/miR-20b-5p/SLC7A11 axis. Methods C57BL/6 mice ( n = 10 per group) were randomly allocated into nine groups, including normal control, SAP model, and various intervention groups involving Homo treatment, circDNMT3B knockdown, and miR-20b-5p inhibition. SAP was induced via caerulein and LPS injections. Assessments included histopathological evaluation, serum analysis (amylase, cytokines IL-1β, IL-6, IL-18), measurement of ferroptosis markers (MDA, GSH, tissue iron), Western blotting for ferroptosis-related proteins (ACSL4, COX-2, SLC7A11, GPX4), and qRT-PCR for gene expression. The targeting relationship between miR-20b-5p and SLC7A11 was validated by dual-luciferase reporter assay. Results SAP mice demonstrated severe pancreatic injury and hallmarks of ferroptosis, including elevated inflammation, iron accumulation, increased ACSL4/COX-2 expression, and upregulation of miR-20b-5p, alongside suppressed SLC7A11 and GPX4. Homo treatment significantly mitigated pancreatic damage and reversed these ferroptosis-related changes. CircDNMT3B knockdown exacerbated SAP severity and attenuated the protective effect of Homo, indicating its dependence on circDNMT3B. Furthermore, the detrimental effects of circDNMT3B knockdown were partially rescued by concurrent inhibition of miR-20b-5p, suggesting that miR-20b-5p acts downstream of circDNMT3B within the protective pathway mediated by Homo. The dual-luciferase assay confirmed miR-20b-5p directly targets SLC7A11. Conclusion Our study demonstrates that Homo protects against SAP primarily by suppressing ferroptosis. Mechanistically, Homo upregulates circDNMT3B, which sequesters miR-20b-5p, thereby relieving its repression of SLC7A11, which in turn supports the GPX4-mediated antioxidant defense. These findings elucidate a novel molecular pathway in SAP-associated ferroptosis and highlight the circDNMT3B/miR-20b-5p/SLC7A11 axis as a promising therapeutic target.
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高影响因子
Small
·
2023
·Vol. 19
·期 16
·2206124
·
IF 13.3
Futing Yang,Wenjie Yu,Qiying Yu,Xiyu Liu,Chunping Liu,Chong Lu,Xinghua Liao,Yi Liu,Na Peng
The apoptosis-resistant mechanism of photodynamic therapy (PDT) usually results in limited therapeutic efficacy. The development of new strategies for sensitizing targeted ferroptosis that bypass apoptosis resistance is of great significance to improve the antitumor efficacy of PDT. In this study, a novel amphiphilic copolymer whose main chain contains reactive oxygen species (ROS)-responsive groups and the end of side chains contains triphenylphosphine is synthesized, to encapsulate porphyrinic metal–organic framework PCN-224 via self-assembly which are hydrothermally synthesized by coordination of zirconium (IV) with tetra-kis(4-caboxyphenyl) porphyrin, and loaded carbon monoxide releasing molecule 401 (CORM-401) by their hollow structures (PCN-CORM), and finally, surface-coated with hyaluronic acid. The nanosystem can sequentially localize to mitochondria which is an important target to induce apoptosis and ferroptosis in cancer cells. Upon excitation with near-infrared light, PCN-224 is activated to produce amounts of ROS, and simultaneously triggers the rapid intracellular release of CO. More importantly, the released CO can sensitize ferroptosis and promote apoptosis to significantly enhance the antitumor efficacy of PCN-224 both in vitro and in vivo. These results illustrate that the mitochondria-targeted drug delivery system combined PDT with CO leads to an effective antitumor efficacy, which maybe a promising way to enhance the treatment efficiency of PDT.
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International Journal of Nanomedicine
·
2022
·
IF 7.033
Xiao Zhao,Ying Wang,Tingting Zhu,Huili Wu,Diya Leng,Zhiguo Qin,Yan Li,Daming Wu
Background Mesoporous calcium-silicate nanoparticles (MCSNs) are advanced biomaterials that have been used to control drug delivery for many years. Ultrasmall Prussian blue nanoparticles (UPBNPs) showed high peroxidase and catalase-like activities. This study evaluated the antibacterial and antibiofilm properties, mechanism and cytotoxicity of UPBNPs-MCSNs composites synthesized by both as precursors. Methods UPBNPs-MCSNs were prepared and characterized. The antibacterial effect of UPBNPs-MCSNs was evaluated by the MTT assay and CFU counting method, and their biosafety was tested by CCK8. Then explore the antibacterial mechanism, including TEM observation of bacterial morphology, and detection of bacterial ROS, LPO and GSH levels. The antibiofilm activity of UPBNPs-MCSNs was tested by E. faecalis biofilm model in human roots. The roots were pretreated with materials and cultured with E. faecalis , and the survival of E. faecalis on the root canal wall was observed by SEM and CLSM. Results The results showed that UPBNPs-MCSNs had potent antibacterial and antibiofilm activities. They can aggregate on the dentin surface and significantly inhibit E. faecalis adhesion and colonization. Their antibacterial activity is as effective as NaClO and calcium hydroxide (CH), can significantly prolong the time of bacterial colonization than CH, but have lower cytotoxicity to normal cells. We found that UPBNPs-MCSNs trigger a like classic ferroptosis pathway in bacteria. UPBNPs-MCSNs can induce bacteria to produce ROS and LPO, and reduce GSH level. Moreover, we observed that the metal ions chelator and the antioxidant could block their antibacterial activity. Conclusion These results reveal that UPBNPS-MCSNs have high antibacterial and antibiofilm, and can mediate the bacterial redox pathway ROS/GSH like the classical pathway of ferroptosis, providing a theoretical basis for them to develop into a safe and effective novel root canal disinfectant.
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高影响因子
APOPTOSIS
·
2023
·Vol. 28
·期 3
·607-626
·
IF 7.2
Yu Li-Ming,Dong Xue,Huang Tao,Zhao Ji-Kai,Zhou Zi-Jun,Huang Yu-Ting,Xu Yin-Li,Zhao Qiu-Sheng,Wang Zhi-Shang,Jiang Hui,Yin Zong-Tao,Wang Hui-Shan
Ferroptosis contributes to the pathogenesis of atrial fibrillation (AF), although the mechanisms are still largely uncovered. The current study was designed to explore the pharmacological effects of icariin against ethanol-induced atrial remodeling, if any, and the mechanisms involved with a focus on SIRT1 signaling. Excessive ethanol-treated animals were administered with Ferrostatin-1, Erastin or icariin to evaluate the potential effects of icariin or ferroptosis. Then, the underling mechanisms was further explored in the in vitro experiments using HL-1 atrial myocytes. Excessive ethanol administration caused significant atrial damage as evidenced by increased susceptibility to AF, altered atrial conduction pattern, atrial enlargement, and enhanced fibrotic markers. These detrimental effects were reversed by Ferrostatin-1 or icariin treatment, while Erastin co-administration markedly abolished the beneficial actions conferred by icariin. Mechanistically, ethanol-treated atria exhibited markedly up-regulated pro-ferroptotic protein (PTGS2, ACSL4, P53) and suppressed anti-ferroptotic molecules (GPX4, FTH1). Icariin treatment inhibited ethanol-induced atrial ferroptosis by reducing atrial mitochondrial damage, ROS accumulation and iron overload. Interestingly, the in vivo and in vitro data showed that icariin activated atrial SIRT1-Nrf-2-HO-1 signaling pathway, while EX527 not only reversed these effects, but also abolished the therapeutic effects of icariin. Moreover, the stimulatory effects on GPX4, SLC7A11 and the suppressive effects on ACSL4, P53 conferred by icariin were blunted by EX527 treatment. These data demonstrate that ferroptosis plays a causative role in the pathogenesis of ethanol-induced atrial remodeling and susceptibility to AF. Icariin protects against atrial damage by inhibiting ferroptosis via SIRT1 signaling. Its role as a prophylactic/therapeutic drug deserves further clinical study.
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Nanoscale
·
2022
·Vol. 14
·期 23
·8441-8453
·
IF 8.307
Dongsheng Zhang,Yanfei Meng,Yingzi Song,Ping Cui,Zunfu Hu,Xiuwen Zheng
With the advancement and development of nanomedicine, tumor precision therapy provides technical support for effective accumulation and targeted drug delivery, and reduces toxic side effects. In cancer cells, breaking the redox balance could induce cancer cell death. Herein, a novel iron-containing intelligent hydrogel nanobot (FeSe2–Ce6/MOF@HA/PEI/CpG@HHPA NPs, abbreviated as FSMH) is proposed to break the intracellular redox balance and trigger the immune response. The as-fabricated multifunctional FSMH could not only exert Fenton reactions in the acidic tumor microenvironment, converting hydrogen peroxide (H2O2) into highly toxic hydroxyl radicals (˙OH), but also effectively consume GSH to attenuate the intracellular oxidative stress. The negative charge of the FSMH nanohydrogel system guarantees its superexcellent stabilization in blood circulation and optimal tumor collection. Subsequently, the surface charge of the endocytosed FSMH was transformed to a positive charge after exposure to the acidic tumor environment, further improving its tumor collection and locally releasing Fe ions and immune adjuvants. Furthermore, Ce6 was released in a pH-responsive manner in the acidic microenvironment. In the presence of near-infrared light, singlet oxygen was produced by the FSMH nanohydrogel system, to ablate tumors and promote the maturation of dendritic cells, achieving the precision-combined strategies effect of CDT, PDT, and immunotherapy.
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FEBS Journal
·
2021
·Vol. 289
·期 7
·1968-1983
·
IF 5.542
Ting-Ting Wei,Meng-Yuan Zhang,Xin-Hua Zheng,Tian-Hua Xie,Wenjuan Wang,Jian Zou,Yan Li,Hong-Ying Li,Jiping Cai,Xiaolu Wang,Jianxin Tan,Xusheng Yang,Yong Yao,Lingpeng Zhu
Retinal pigment epithelium (RPE) cell damage is implicated in the pathogenesis of age-related macular degeneration (AMD). An increase of interferon-γ (IFN-γ) levels was observed in patients with AMD, but whether inflammatory factors are causally related to AMD progression is unclear. Here, we demonstrate a direct causal relationship between IFN-γ and RPE cell death. IFN-γ induced human retinal pigment epithelial cell (ARPE-19) death accompanied by increases in Fe 2+ , reactive oxygen species, lipid peroxidation, and glutathione (GSH) depletion, which are main characteristics of ferroptosis. Mechanistically, IFN-γ upregulates the level of intracellular Fe 2+ through inhibiting Fe 2+ efflux protein SLC40A1 and induces GSH depletion by blocking cystine/glutamate antiporter, System xc-. At the same time, treatment with IFN-γ decreases the level of glutathione peroxidase 4 (GPx4), rendering the cells more sensitive to ferroptosis. JAK1/2 and STAT1 inhibitors could reverse the reduction of SLC7A11, GPx4 and GSH expression induced by IFN-γ, indicating IFN-γ induces ARPE-19 cell ferroptosis via activation of the JAK1-2/STAT1/SLC7A11 signaling pathway. The above results were largely confirmed in IFN-γ-treated mice in vivo . Finally, we used sodium iodate (NaIO 3 )-induced retinal degeneration to further explore the role of ferroptosis in AMD in vivo . Consistent with the role of IFN-γ, treatment with NaIO 3 decreased SLC7A11, GPx4 and SLC40A1 expressions. NaIO 3 -induced RPE damage was accompanied by increased iron, lipid peroxidation products (4-hydroxynonenal, malondialdehyde), and GSH depletion, and ferroptosis inhibitors could reverse the above phenomenon. Taken together, our findings suggest that inhibiting ferroptosis or reducing IFN-γ may serve as a promising target for AMD.
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CHEMICAL ENGINEERING JOURNAL
·
2024
·
IF 13.3
Chun-Mei Lai,Jia Xu,Bing-Chen Zhang,Shao-Hua He,Jing-Wei Shao
Ferroptosis, an emerging cell death mode discovered in recent decades, is characterized by lipid peroxidation during cell death, usually manifested as iron accumulation. However, the forthright delivery of iron species will cause adverse detrimental effects such as anaphylactic reactions in routine tissues. So far, studies on cellular ferroptosis by employing bio-derived nanomaterials have rarely been acquired. Herein, we reported carbon dots (CDs)-based biocompatible enzymes with negligible toxicity from a representative hepatoprotective triterpenoid natural product ursolic acid (UA) with acknowledged antitumor activity. We observed that CDs presented distinct GSH oxidase-like characteristics and then contributed ferroptosis of carcinoma cells by interfering with the GPX4-catalyzed lipid repair system. After the CDs were assembled with UA, the obtained denoted as UCDs integrated multi-model therapy into one, resulting in enhanced therapeutic efficacy, reduced adverse effects, and optimized clinical outcomes. In vivo , the UCDs hysterically inhibited tumor growth in hepatoma H22-bearing mice with inconsequential toxicity. Exceptionally, UCDs enlisted a large number of tumor-infiltrating immune cells, including T cells, NK cells, and macrophages in H22 tumor-bearing mice, consequently transforming “cold” into “hot” tumors to activate systemic anti-tumor immune responses. Meanwhile, UCDs could also awfully suppress the H22-LUC tumor growth in orthotopic xenograft mouse models. Collectively, our research commends that the drug delivery systems based on natural-products-derived CDs can function as biocompatible enzymes for antitumor treatment and may facilitate the advancement of nanotechnology-based immunotherapeutics. It is extremely anticipated that such ferroptosis-like designing in nano-catalytic medicine would be favorable for future development in cancer-therapeutic regimens.
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ACS Nano
·
2023
·
IF 17.1
Wanrui Shi,Wenjie Feng,Siyuan Li,Yanqi Cui,Shuwei Liu,Huan Jiang,Yi Liu,Hao Zhang
Nanovaccine-based immunotherapy has been considered as a major pillar to stimulate the host immune system to recognize and eradicate tumor cells as well as establish a long-term immune memory to prevent tumor relapse and metastasis. However, the weak specificity and low cross-presentation of antigens, as well as the immunosuppressive microenvironments of tumor tissues, are still the major obstacles on exerting the therapeutic performance of tumor nanovaccines sufficiently. Herein, we design and construct cytosine guanine dinucleotide (CpG) oligodeoxynucleotide (ODN)-loaded aluminum hydroxyphosphate nanoparticles covered by Fe-Shikonin metal-phenolic networks (MPNs) (Alum-CpG@Fe-Shikonin NPs) as personalized in situ nanovaccines for antitumor immunity. Upon internalization by tumor cells, the shell of Fe-Shikonin MPNs will disassemble into Fe2+ and Shikonin to elicit the immunogenic cell death of tumor cells through ferroptosis and necroptosis. Then, dying tumor cell-released autologous tumor cell lysates will be absorbed by Alum NPs and codelivered with CpG ODN to professional antigen-presenting cells temporally and spatially to activate multistep cascade antitumor immune responses, including dendritic cell maturation, antigen cross-presentation, natural killer cell and cytotoxic T lymphocyte infiltrations, and tumor-associated macrophage repolarization. Benefiting from the synergistic effects of Alum NPs, CpG ODN, and Fe-Shikonin MPNs, our Alum-CpG@Fe-Shikonin NPs exhibit drastic cytotoxicity and accurate selectivity on eradicating primary tumor, strong abscopal effect on inhibiting distant tumor, and a long-term immune memory effect on preventing tumor metastasis and recurrence. Because our report provides a feasible strategy to in situ make full use of autologous tumor cell lysates, which present an entire spectrum of the patient’s personal epitopes without complicated ex vivo processes, such as extraction, purification, and sequencing, it may promote the development of personalized nanovaccines for antitumor immunity.
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JOURNAL OF CONTROLLED RELEASE
·
2023
·
IF 10.8
Xin Yang,Wanqiong Li,Shuzhen Li,Shaomeng Chen,Zheng Hu,Zhuoying He,Xueqin Zhu,Xiaoshuang Niu,Xiuman Zhou,Huihao Li,Youmei Xiao,Juan Liu,Xinghua Sui,Guanyu Chen,Yanfeng Gao
Peptide immune checkpoint inhibitors in cancer immunotherapy have attracted great attention recently, but oral delivery of these peptides remains a huge challenge due to the harsh gastrointestinal environment, large molecular size, high hydrophilic, and poor transmembrane permeability. Here, for the first time, a fish oil-based microemulsion was developed for oral delivery of programmed death-1/programmed cell death-ligand 1 (PD-1/PD-L1) blocking model peptide, OPBP-1. The delivery system was characterized, in vitro and in vivo studies were conducted to evaluate its overall implication. As a result, this nutraceutical microemulsion was easily formed without the need of co-surfactants, and it appeared light yellow, transparent, good flowability with a particle size of 152 ± 0.73 nm, with a sustained drug release manner of 56.45 ± 0.36% over 24 h and a great stability within the harsh intestinal environment. It enhanced intestinal drug uptake and transportation over human intestinal epithelial Caco-2 cells, and drastically elevated the oral peptide bioavailability of 4.1-fold higher than that of OPBP-1 solution. Meanwhile, the mechanism of these dietary droplets permeated over the intestinal enterocytic membrane was found via clathrin and caveolae-mediated endocytic pathways. From the in vivo studies, the microemulsion facilitated the infiltration of CD8 + T lymphocytes in tumors, with increased interferon-γ (IFN-γ) secretion. Thus, it manifested a promising immune anti-tumor effect and significantly inhibited the growth of murine colonic carcinoma (CT26). Furthermore, it was found that the fish oil could induce ferroptosis in tumor cells and exhibited synergistic effect with OPBP-1 for cancer immunotherapy. In conclusion, this fish oil-based formulation demonstrated great potential for oral delivery of peptides with its natural property in reactive oxygen species (ROS)-related ferroptosis of tumor cells, which provides a great platform for functional green oral delivery system in cancer immunotherapy.
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