小鼠中通过链转移反应增强脂质过氧化用于磁共振成像指导的癌症治疗

Lipid peroxidation(LPO),the process of membrane lipid oxidation,is a potential new form of cell death for cancer treatment.However,the radical chain reaction involved in LPO is comprised of the initiation,propagation(the slowest step),and termination stages,limiting its effectiveness in vivo.To address this limitation,we introduce the radical chain transfer reaction into the LPO process to target the propagation step and overcome the sluggish rate of lipid peroxidation,thereby promoting endogenous lipid peroxidation and enhancing therapeutic outcomes.Firstly,radical chain transfer agent(CTA-1)/Fe nanoparticles(CTA-Fe NPs-1)was synthesized.Notably,CTA-1 convert low activity peroxyl radicals(ROO·)into high activity alkoxyl radicals(RO·),creating the cycle of free radical oxidation and increasing the propagation of lipid peroxidation.Additionally,CTA-1/Fe ions enhance reactive oxygen species(ROS)generation,consume glutathione(GSH),and thereby inactivate GPX-4,promoting the initiation stage and reducing termination of free radical reaction.CTA-Fe NPs-1 induce a higher level of peroxidation of polyunsaturated fatty acids in lipid membranes,leading to highly effective treatment in cancer cells.In addition,CTA-Fe NPs-1 could be enriched in tumors inducing potent tumor inhibition and exhibit activatable T1-MRI contrast of magnetic resonance imaging(MRI).In summary,CTA-Fe NPs-1 can enhance intracellular lipid peroxidation by accelerating initiation,propagation,and inhibiting termination step,promoting the cycle of free radical reaction,resulting in effective anticancer outcomes in tumor-bearing mice.

Engineering Cell-Selective Charge-Altering Lipid Nanoparticles for Efficient siRNA Delivery in Vivo

Lipid nanoparticles(LNPs)have emerged as a powerful platform for RNA delivery;the chemical engineering of LNP for efficient delivery of RNA into cytosol remains critical but challenging.One promising strategy is the use of permanently positively charged lipids,which have been shown to enhance the stability and delivery efficiency of LNPs.However,the resulting strong electrostatic interactions reduced the RNA release capacity from the lipoplexes.Herein,we engineered a hydrogen peroxide(H_(2)O_(2))-triggered charge-altering LNP(CALNP)for efficient small interfering RNA(siRNA)delivery and tumor therapy in mice.The incorporation of phenylboronic acid(PBA)into ionizable lipids generated permanently positively charged lipids.A CALNP with optimal lipid formulations was identified,exhibiting enhanced transfection efficiency with effective lysosomal escape through dual effects of electrostatic interaction and ligand-receptor binding.H_(2)O_(2)-triggered removal of PBA groups regenerated ionizable LNP with reduced positive charges at physiological pH,allowing cell-selective siRNA release in the cytoplasm.Our results demonstrated that CALNPs exhibited improved siRNA transfection and gene silencing efficiency.We also showed potent CALNP activity against the polo-like kinase 1(Plk1)gene by effectively silencing Plk1 mRNA and subsequent suppression of tumor growth.Collectively,these findings highlighted the potential of CALNP as an efficient platform for RNA delivery and tumor therapeutics.

Imaging Carotid Plaque Burden in Living Mice via Hybrid Semiconducting Polymer Nanoparticles-Based Near-Infrared-II Fluorescence and Magnetic Resonance Imaging

The majority of atherothrombotic events (e.g., cerebral or myocardial infarction) often occur as a result of plaque rupture or erosion in the carotid, and thereby it is urgent to assess plaque vulnerability and predict adverse cerebrovascular events. However, the monitoring evolution from stable plaque into life-threatening high-risk plaque in the slender carotid artery is a great challenge, due to not enough spatial resolution for imaging the carotid artery based on most of reported fluorescent probes. Herein, copolymerizing with the small molecules of acceptor-donor-acceptor-donor-acceptor (A-D-A′-D-A) and the electron-donating units (D′), the screened second near-infrared (NIR-II) nanoprobe presents high quantum yield and good stability, so that it enables to image slender carotid vessel with enough spatial resolution. Encouragingly, NIR-II nanoprobe can effectively target to intraplaque macrophage, meanwhile distinguishing vulnerable plaque in carotid atherosclerosis in living mice. Moreover, the NIR-II nanoprobe can dynamically monitor the fresh bleeding spots in carotid plaque, indicating the increased risk of plaque instability. Besides, magnetic resonance imaging is integrated with NIR-II fluorescence imaging to provide contrast for subtle structure (e.g., narrow lumen and lipid pool), via incorporating ultrasmall superparamagnetic iron oxide into the NIR-II nanoprobe. Thus, such hybrid NIR-II/magnetic resonance imaging multimodal nanoprobe provides an effective tool for assessing carotid plaque burden, selecting high-risk plaque, and imaging intraplaque hemorrhage, which is promising for reducing cerebral/ myocardial infarction-associated morbidity and mortality.