Targeted Oxygenation System Remodel Tumor Microenvironment For Tumor Immune Regulation And Therapy

Tumor metastasis has become the leading challenge in current clinical cancer treatments,accounting for over 90%of all cancer-caused deaths.Particularly,metastatic triple-negative breast cancer?mTNBC?is nearly the most fatal breast cancer subtype due to its high recurrence rate,distant metastasis,and poor prognosis.An ideal cancer therapeutic strategy is expected to possess potent ability to not only ablate primary tumors but also prevent distance metastasis and relapse.Photodynamic therapy?PDT?has emerged as an ideal and effective therapeutic modality with advantages in great spatiotemporal selectivity and minimal invasiveness strategy for cancer treatment,which kills cancer cells by employing photosensitizers and oxygen to generate singlet oxygen under light irradiation.However,due to the abnormal proliferation of the vascular system in solid tumor tissues,normal blood circulation cannot be formed,and solid tumors often develop a specialized hypoxic microenvironment.Local hypoxic tumor microenvironment not only greatly limits the PDT efficacy,but also has an association with tumor invasiveness and metastasis.Therefore,it is particularly important to develop a safe and effective tumor site-specific oxygenation strategy to improve the PDT efficacy against the primary tumor,metastases,and recurrence.In the current project,manganese dioxide capable of tumor microenvironment responsive in situ oxygenation and Cyanobacteria capable of photocatalyzed oxygen generation are selected as oxygen producers to improve the tumor microenvironment through targeted tumor oxygenation for oxygen-boosted PDT,which elicit immunogenic cell death?ICD?and stimulate antitumor immune response to inhibit tumor metastasis and recurrence.Multi-modality imaging are employed to monitor the tumor targeting oxygen supply efficiency.The effect of oxygen-intervening PDT is determined and the mechanism of ICD-based anti-cancer immune response induced by oxygen-intervening PDT is clarified.The results of this study will not only provide an effective method to overcome tumor hypoxia,but also provide a promising immunogenic PDT strategy for anti-cancer treatment.1.The core-shell gold nanocage@manganese dioxide?AuNC@MnO2,AM?nanoparticles as tumor microenvironment responsive in situ oxygen producers for oxygen-boosted immunogenic PDT against tumor growth and metastasis.In this project,we employed a template method to fabricate the core-shell gold nanocage@manganese dioxide?AuNC@MnO₂,AM?nanoparticles as tumor microenvironment responsive oxygen producers and near-infrared?NIR?-triggered reactive oxygen species?ROS?generators for oxygen-boosted immunogenic PDT against tumor growth and metastasis.The size,composition and properties of gold nanocage are tuned by controlling the reaction time and the ratio among the reactors.Gold nanocage as the core play the role in photodynamic and photothermal therapy under NIR radiation.MnO₂ as the shell trigger the tumor-specific oxygen generation in acid and hydrogen peroxide?H₂O₂?-rich tumor microenvironment,which overcome tumor hypoxia and boost PDT effect.Fluorescence?FL?/photoacoustic?PA?/magnetic resonance?MR?multimodal imaging confirms the effective accumulation of AM nanoparticles with sufficient oxygenation in tumor site to ameliorate local hypoxia.Moreover,the oxygen-boosted PDT effect of AM not only destroys primary tumor effectively but also elicits immunogenic cell death?ICD?with damage-associated molecular patterns?DAMPs?release and exposure,which subsequently induces DC maturation and effector cells activation,thereby robustly evoking systematic antitumor immune responses against tumor growth and metastasis in a 4T1 mTNBC murine model.Hence,this oxygen-boosted immunogenic PDT?iPDT?nanosystem offers a promising approach to ablate primary tumor and simultaneously prevent tumor metastases via immunogenic abscopal effects.Related results were publicated in Biomaterials?2018,177,149?,Acta Biomaterialia?2020,104,188?,and applied for one national patent.2.Active photosynthetic cyanobacteria?Syne?-delivered HSA/ICG NPs?S/HSA/ICG?biomimetic system for in situ photocatalyzed oxygen generation to achieve photosynthesis-boosted immunogenic PDT against tumor growth and metastasis.Herein,active photosynthetic bacteria?Syne?are utilized for tumor-targeted photosensitizer delivery and in situ photocatalyzed oxygen generation to achieve photosynthesis-boosted PDT.Photosensitizer-encapsulated nanoparticles?HSA/ICG?are assembled by intermolecular disulfide crosslinking and attached to the surface of Syne with amide bonds to form a biomimetic system?S/HSA/ICG?.S/HSA/ICG combined the photosynthetic capability of Syne and the theranostic effect of HSA/ICG.Syne capable of photoautotrophy exhibit a moderate immune stimulation effect and a certain photodynamic role under 660 nm laser irradiation.Upon intravenous injection into tumor-bearing mice,S/HSA/ICG can effectively accumulate in tumors and generate oxygen continuously under laser irradiation through photosynthesis,which remarkably relieve tumor hypoxia and enhance reactive oxygen species production,thereby completely eliminating primary tumors.This photosynthesis-boosted PDT can also effectively reverse the tumor immunosuppressive microenvironment and robustly evoke ICD-mediated systematic antitumor immune responses,which exhibit excellent effect on preventing tumor recurrence and metastasis inhibition in a 4T1 mTNBC murine model.Hence,this photosynthetic bacteria-based photosynthesis-boosted immunogenic PDT offers a promising approach to eliminate both local and metastatic tumors.Related results were publicated in Advanced Functional Materials?2020,1910176?,and applied for two national patents.