Despite the promising potential of organic nanoscintillator-mediated radiodynamic therapy(RDT)in enhancing the effectiveness of immunotherapy,their cutaneous phototoxicity exacerbates the risk for immune-related adver...Despite the promising potential of organic nanoscintillator-mediated radiodynamic therapy(RDT)in enhancing the effectiveness of immunotherapy,their cutaneous phototoxicity exacerbates the risk for immune-related adverse events(irAEs).Herein,we demonstrate that organic nanoscintillators,when combined with checkpoint blockade immunotherapy and exposed to X-ray-induced RDT,can trigger cutaneous irAEs.To address this challenge,we engineered diselenide-bridged silicon coatings on organic nanoscintillators,fine-tuning the steric hindrance of the protective layer by varying its thickness.This strategy enables radiation-triggered reactive oxygen species(ROS)generation while mitigating off-target phototoxicity through neutralizing ROS.By optimizing the steric hindrance to precisely control energy transfer between the organic nanoscintillators and surrounding oxygen molecules,we effectively reduce phototoxicity and mitigate off-tumor effects through engineered surface protection.Under X-ray irradiation exposure,the steric hindrance is rapidly deactivated through the dissociation of the silicon coating,activating RDT and inducing abundant ROS generation within tumor cells.In an orthotopic 4T1 breast cancer model,intravenous administration of these surface-engineered nanoscintillators,combined with anti-programmed death-1(anti-PD-1)antibodies,results in robust anti-tumor immune responses,while minimizing cutaneous irAEs.This work offers valuable insights into how surface engineering can modulate the delicate balance between anti-tumor efficacy and off-tumor toxicity in nanoscintillator-mediated RDT.展开更多
Sound pollution(noise) is an increasing environmental concern,particularly associated with neurological and neurobehavioral abnormalities.However,the molecular mechanisms underlying noise-induced neural damage remain ...Sound pollution(noise) is an increasing environmental concern,particularly associated with neurological and neurobehavioral abnormalities.However,the molecular mechanisms underlying noise-induced neural damage remain unclear.In this study,we conducted transcriptional profiling of zebrafish to investigate the mechanisms underlying acoustic stimulation(1,000 Hz,130 d B).RNA sequencing and subsequent experiments revealed that TRPV1 is an important mediator of noise-induced neural damage in Hu C(elavl3)-GFP transgenic zebrafish.The results demonstrated that inhibiting TRPV1 significantly mitigated noise-induced neural damage in zebrafish with trpv1 gene RNAi and in mice with Trpv1 knockout(Trpv1~(-/-)).Specifically,TRPV1 antagonism significantly reduced neural damage in zebrafish and mice under noise exposure.Furthermore,activated TRPV1 could induce endoplasmic reticulum stress,leading to apoptosis and resulting in neural damage in mice and HEK293T cells.The findings of this study not only enhance our understanding of the molecular mechanisms underlying sound-induced neural damage but also highlight a novel target for drug intervention.展开更多
基金supported by the Science and Technology Program of Guangzhou(No.2023A03J0218)。
文摘Despite the promising potential of organic nanoscintillator-mediated radiodynamic therapy(RDT)in enhancing the effectiveness of immunotherapy,their cutaneous phototoxicity exacerbates the risk for immune-related adverse events(irAEs).Herein,we demonstrate that organic nanoscintillators,when combined with checkpoint blockade immunotherapy and exposed to X-ray-induced RDT,can trigger cutaneous irAEs.To address this challenge,we engineered diselenide-bridged silicon coatings on organic nanoscintillators,fine-tuning the steric hindrance of the protective layer by varying its thickness.This strategy enables radiation-triggered reactive oxygen species(ROS)generation while mitigating off-target phototoxicity through neutralizing ROS.By optimizing the steric hindrance to precisely control energy transfer between the organic nanoscintillators and surrounding oxygen molecules,we effectively reduce phototoxicity and mitigate off-tumor effects through engineered surface protection.Under X-ray irradiation exposure,the steric hindrance is rapidly deactivated through the dissociation of the silicon coating,activating RDT and inducing abundant ROS generation within tumor cells.In an orthotopic 4T1 breast cancer model,intravenous administration of these surface-engineered nanoscintillators,combined with anti-programmed death-1(anti-PD-1)antibodies,results in robust anti-tumor immune responses,while minimizing cutaneous irAEs.This work offers valuable insights into how surface engineering can modulate the delicate balance between anti-tumor efficacy and off-tumor toxicity in nanoscintillator-mediated RDT.
基金supported by the National Natural Science Foundation of China (32270813)Young Scientists Fund of the National Natural Science Foundation of China (22305173)+2 种基金National Key R&D Program of China (2023YFC3605305)Beijing NOVA Program (20220484230)Youth Innovation Science Fund,PLA General Hospital (22QNCZ016)。
文摘Sound pollution(noise) is an increasing environmental concern,particularly associated with neurological and neurobehavioral abnormalities.However,the molecular mechanisms underlying noise-induced neural damage remain unclear.In this study,we conducted transcriptional profiling of zebrafish to investigate the mechanisms underlying acoustic stimulation(1,000 Hz,130 d B).RNA sequencing and subsequent experiments revealed that TRPV1 is an important mediator of noise-induced neural damage in Hu C(elavl3)-GFP transgenic zebrafish.The results demonstrated that inhibiting TRPV1 significantly mitigated noise-induced neural damage in zebrafish with trpv1 gene RNAi and in mice with Trpv1 knockout(Trpv1~(-/-)).Specifically,TRPV1 antagonism significantly reduced neural damage in zebrafish and mice under noise exposure.Furthermore,activated TRPV1 could induce endoplasmic reticulum stress,leading to apoptosis and resulting in neural damage in mice and HEK293T cells.The findings of this study not only enhance our understanding of the molecular mechanisms underlying sound-induced neural damage but also highlight a novel target for drug intervention.
