| 摘要: | 隨著癌症發病率逐年上升，傳統治療方式如手術、化 療與放療雖在臨床上廣泛應用，但往往存在嚴重副作用、治療耐受性高及腫瘤復發率高等問題，尤其對於晚期或轉移性腫瘤患者，治療效果更顯有限。因此，開發更具靶向性、低毒性且能激活免疫系統的新型療法成為當前癌症研究的重點方向。
癌症免疫療法近年來徹底改變了腫瘤學的治療格局。在眾多新興策略中，微生物介導的腫瘤療法（Microbial-Mediated Tumor Therapies, MMTT）因其有望克服對傳統治療的抗性而備受關注。然而，這類療法仍面臨重大挑戰，包括：藥物傳遞過程中使患者不必要的發炎反應、抗生素抗性基因傳播的疑慮，以及臨床應用前難以滅菌的問題。
本研究主要利用本實驗室獨創原位水相包覆酵素方式，將酵素換成活的大腸桿菌（Escherichia coli, E. coli）以單晶完整包覆封裝—類沸石咪唑骨架材料-90（ZIF-90）MOF材料中並此生物複合體具備強化抗紫外線與抗抗生素能力，且幾乎不引發免疫刺激反應，此些優勢可以克服當今微生物介導的腫瘤療法最大的困境。此ZIF-90系統與另一個類似的類沸石咪唑骨架材料-8（ZIF-8）封裝後比較後由於ZIF-90具有完整封裝的特性表現明顯優於傳統ZIF-8塗層方式。
在細胞實驗中發現ZIF-90單晶封裝大腸桿菌的生物複合材料（E. coli@ZIF-90）在pH 6.0微酸環境下會崩解外層MOF釋放出內部細菌同時保有免疫活化能力。並在癌症細胞篩選上對乳腺癌細胞有較顯著的抑制能力，對正常乳腺細胞則無任何殺傷力。透過細胞吞噬能力證實E. coli@ZIF-90對癌症細胞優異的選擇性。實驗進一步證實對癌症細胞抑制能力來自大腸桿菌外膜上的脂多醣（Lipopolysaccharide, LPS）誘導細胞焦亡（pyroptosis）的治療方法。
在老鼠動物實驗中，證實E. coli@ZIF-90可引發免疫反應導致脾臟腫大、透過誘導細胞焦亡減少肺部腫瘤結節，並展現出明確的靶向遞送能力。與LPS@ZIF-90不同，E. coli@ZIF-90可有效上調與焦亡相關的信號通路。
此系統也與現今常用的癌症治療藥物進行比較，發現E. coli@ZIF-90與Taxol以及Carboplatin做為治療癌症藥物相比有不俗的抗癌能力 ，除此之外還表現出免疫增強的效果，相比傳統癌症治療藥物，E. coli@ZIF-90可以發揮更長效的治療。這項研究在癌症治療研究中做出了重要貢獻，提供了不一樣的治療可能性。總之，上述研究顯示金屬有機框架（MOF）封裝是一種提升細菌療法在癌症免疫治療中效果的有前景策略。
;As cancer incidence rises annually, traditional treatments like surgery, chemotherapy, and radiotherapy, though common, often cause severe side effects, high drug resistance, and recurrence-particularly in advanced or metastatic cases. Thus, current research focuses on developing targeted, less toxic therapies that also activate the immune system. Cancer immunotherapy has recently transformed oncology, with MMTT standing out for their ability to bypass resistance to traditional treatments. Yet, MMTT still faces key hurdles, including off-target inflammation, risk of antibiotic resistance gene transmission, and sterilization challenges prior to clinical use.
In this study, we developed a novel approach by encapsulating live Escherichia coli within a single crystal of Zeolitic Imidazolate Framework-90 (ZIF-90) using a de novo, water-based method. This single-crystalline MOF-bacteria composite enhances resistance to UV and antibiotics while minimizing immune stimulation-effectively addressing key challenges in microbial-mediated tumor therapies. Compared to conventional ZIF-8 surface coating, the fully encapsulated E. coli@ZIF-90 exhibited significantly superior protective performance.
Under mildly acidic conditions (pH 6.0), which mimic the tumor microenvironment, the ZIF-90 shell selectively degrades, leading to the controlled release of viable bacteria while preserving their immunostimulatory properties. In vitro assays demonstrated that E. coli@ZIF-90 selectively inhibited the proliferation of breast cancer cells, while exhibiting negligible cytotoxicity toward normal mammary epithelial cells. This selective effect was further corroborated through phagocytosis assays, which revealed a preferential uptake of E. coli@ZIF-90 by cancer cells. Mechanistic investigations identified lipopolysaccharide (LPS), a key component of the bacterial outer membrane, as the principal factor mediating cancer cell death via pyroptosis—a caspase-dependent pro-inflammatory cell death pathway.
In vivo experiments using murine models further validated the therapeutic potential of this platform. Administration of E. coli@ZIF-90 induced a systemic immune response, as evidenced by splenic enlargement, and significantly reduced the number of tumor nodules in lung tissue through pyroptosis induction. Moreover, E. coli@ZIF-90 exhibited superior tumor-targeting capabilities and a more pronounced activation of pyroptosis-related signaling pathways compared to LPS@ZIF-90.
When benchmarked against standard chemotherapeutic agents such as Taxol and Carboplatin, E. coli@ZIF-90 demonstrated comparable anti-tumor efficacy. Notably, it also conferred additional immunomodulatory benefits, suggesting the potential for prolonged therapeutic effects beyond those offered by conventional treatments.
In summary, this work highlights the promise of MOF based bacterial encapsulation as a novel and effective strategy to enhance the therapeutic performance of microbial cancer immunotherapy. This platform offers new opportunities for the development of safe, targeted, and immuno-stimulatory cancer treatments. |
