The NIR-IIb (1500-1700 nm) window is ideal for deep-tissue optical imaging in mammals, but lacks bright and biocompatible probes. Here, we developed biocompatible cubic-phase (α-phase) erbium-based rare-earth nanoparticles (ErNPs) exhibiting bright downconversion luminescence at ~ 1600 nm for dynamic imaging of cancer immune-therapy in mice. We used ErNPs functionalized with cross-linked hydrophilic polymer layers attached to anti-PD-L1 antibody for molecular imaging of PD-L1 in a mouse model of colon cancer and achieved tumor to normal tissue signal ratios of ~ 40. The long luminescence lifetime of ErNPs (~ 4.6 ms) enabled simultaneous imaging of ErNPs and lead sulfide quantum dots (PbS QDs) emitting in the same ~ 1600 nm window. In vivo NIR-IIb molecular imaging of PD-L1 and CD8 revealed cytotoxic T *

Deep-tissue three-dimensional (3D) optical imaging of live mammals with high spatiotemporal resolution in non-invasive manners has been challenging due to light scattering. Here, we developed near-infrared II (NIR-II, 1000–1700 nm) light sheet microscopy (LSM) with excitation and emission up to ~ 1320 nm and ~ 1700 nm respectively for optical sectioning through live tissues at ~ 750-μm penetration depth without any invasive surgery. Suppressed light scattering allowed imaging at ~ 2 mm depth in glycerol-cleared brain tissues. NIR-II LSM in normal and oblique configurations enabled in vivo imaging of live mice through intact tissue, revealing abnormal blood flow and T cell motion in tumor microcirculation and mapping out programmed-death ligand 1 (PD-L1) and programmed cell death protein 1 (PD-1) in tumors with cellular resolution. 3D imaging through intact mouse head resolved vascular channels between skull and brain cortex, and monitored recruitment of macrophages/microglia to traumatic brain injury site post injury.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by degeneration of dopaminergic neurons associated with dysregulation of iron homeostasis in the brain. Ferroptosis is an iron-dependent cell death process that serves as a significant regulatory mechanism in PD. However, its underlying mechanisms are not yet fully understood. By performing RNA sequencing analysis, we found that the main iron storage protein ferritin heavy chain 1 (FTH1) is differentially expressed in the rat 6hydroyxdopamine (6-OHDA) model of PD compared with control rats. Our present work demonstrates that FTH1 is involved in iron accumulation and the ferroptosis pathway in this model. Knockdown of FTH1 in PC-12 cells significantly inhibited cell viability and caused mitochondrial dysfunction. Moreover, FTH1 was found to be involved in ferritinophagy, a selective form of autophagy involving the degradation of ferritin by ferroptosis. Overexpression of FTH1 in PC-12 cells impaired ferritinophagy and downregulated microtubule-associated protein light chain 3 and nuclear receptor coactivator 4 expression, ultimately suppressing cell death induced by ferroptosis. Consistent with these findings, the ferritinophagy inhibitors chloroquine and bafilomycin A1 inhibited ferritin degradation and ferroptosis in 6-OHDA-treated PC-12 cells. This entire process was mediated by the cyclic regulation of FTH1 and ferritinophagy. Taken together, these results suggest that FTH1 links ferritinophagy and ferroptosis in the 6-OHDA model of PD, and provide a new perspective and potential for a pharmacological target in this disease.

Fluorescence imaging in the second near-infrared (NIR-II) window holds impressive advantages of enhanced penetration depth and improved signal-to-noise ratio. Bright NIR-II fluorophores with renal excretion ability and low tissue accumulation are favorable for in vivo molecular imaging applications as they can render the target-mediated molecular imaging process easily distinguishable. Here, a probe (anti-PD-L1-BGP6) comprising a fluorophore (IR-BGP6) covalently bonded to the programmed cell death ligand-1 monoclonal antibody (PD-L1 mAb) for molecular imaging of immune checkpoint PD-L1 (a targeting site upregulated in various tumors for cancer imaging) in the NIR-II window is reported. Through molecular optimization, the bright NIR-II fluorophore IR-BGP6 with fast renal excretion (≈91% excretion in general through urine within the first 10 h postinjection) is developed. The conjugate anti-PD-L1-BGP6 succeeds in profiling PD-L1 expression and realizes efficient noninvasive molecular imaging in vivo, achieving a tumor to normal tissue (T/NT) signal ratio as high as ≈9.5. Compared with the NIR-II fluorophore with high nonspecific tissue accumulation, IR-BGP6 derived PD-L1 imaging significantly enhances the molecular imaging performance, serving as a strong tool for potentially studying underlying mechanism of immunotherapy. The work provides rationales to design renal-excreted NIR-II fluorophores and illustrate their advantages for in vivo molecular imaging.

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We describe a novel antibiotic delivery system based on magnetic nanoparticles (NPs) conjugated to a cell-penetrating peptide (CPP).

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The development of hepatocellular carcinomas (HCC) depends on their local microenvironment and the induction of neovascularization is a decisive step in tumor progression, since the growth of solid tumors is limited by nutrient and oxygen supply. Hypoxia is the critical factor that induces transcription of the hypoxia inducible factor-1α (HIF-1α) encoding gene HIF1A and HIF-1α protein accumulation to promote angiogenesis. However, the basis for the transcriptional regulation of HIF1A expression in HCC is still unclear. Here, we show that Bclaf1 levels are highly correlated with HIF-1α levels in HCC tissues, and that knockdown of Bclaf1 in HCC cell lines significantly reduces hypoxia-induced HIF1A expression. Furthermore, we found that Bclaf1 promotes HIF1A transcription via its bZIP domain, leading subsequently to increased transcription of the HIF-1α downstream targets VEGFA, TGFB, and EPO that in turn promote HCC-associated angiogenesis and thus survival and thriving of HCC cells. Moreover, we demonstrate that HIF-1α levels and microvessel density decrease after the shRNA-mediated Bclaf1 knockdown in xenograft tumors. Finally, we found that Bclaf1 levels increase in hypoxia in a HIF-1α dependent manner. Therefore, our study identifies Bclaf1 as a novel positive regulator of HIF-1α in the hypoxic microenvironment, providing new incentives for promoting Bcalf1 as a potential therapeutic target for an anti-HCC strategy.