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Abstract The lack of precise spatiotemporal gene modulation and therapy impedes progress in medical applications. Herein, a 980 nm near‐infrared (NIR) light‐controlled nanoplatform, namely URMT, is developed, which can allow spatiotemporally controlled photodynamic therapy and trigger the enzyme‐activated gene expression regulation in tumors. URMT is constructed by engineering an enzyme‐activatable antisense oligonucleotide, which combined with an upconversion nanoparticle (UCNP)‐based photodynamic nanosystem, followed by the surface functionalization of triphenylphosphine (TPP), a mitochondria‐targeting ligand. URMT allows for the 980 nm NIR light‐activated generation of reactive oxygen species, which can induce the translocation of a DNA repair enzyme (namely apurinic/apyrimidinic endonuclease 1, APE1) from the nucleus to mitochondria. APE1 can recognize the basic apurinic/apyrimidinic (AP) sites in DNA double‐strands and perform cleavage, thereby releasing the functional single‐strands for gene regulation. Overall, an augmented antitumor effect is observed due to NIR light‐controlled mitochondrial damage and enzyme‐activated gene regulation. Altogether, the approach reported in this study offers high spatiotemporal precision and shows the potential to achieve precise and specific gene regulation for targeted tumor treatment.

Abstract Background Radiotherapy (RT) is one of the major therapeutic approaches to hepatocellular carcinoma (HCC). Ionizing radiation (IR) inducing the generation of reactive oxygen species (ROS) leads to a promising antitumor effect. However, the dysregulation of the redox system often causes radioresistance and impairs the efficacy of RT. Increasing evidence indicates that nuclear protein 1 (NUPR1) plays a critical role in redox reactions. In this study, we aim to explore the role of NUPR1 in maintaining ROS homeostasis and radioresistance in HCC. Methods The radioresistant role of NUPR1 was determined by colony formation assay, comet assay in vitro, and xenograft tumor models in vivo. Probes for ROS, apoptosis assay, and lipid peroxidation assay were used to investigate the functional effect of NUPR1 on ROS homeostasis and oxidative stress. RNA sequencing and co-immunoprecipitation assay were performed to clarify the mechanism of NUPR1 inhibiting the AhR/CYP signal axis. Finally, we analyzed clinical specimens to assess the predictive value of NUPR1 and AhR in the radiotherapeutic efficacy of HCC. Results We demonstrated that NUPR1 was upregulated in HCC tissues and verified that NUPR1 increased the radioresistance of HCC in vitro and in vivo. NUPR1 alleviated the generation of ROS and suppressed oxidative stress, including apoptosis and lipid peroxidation by downregulating cytochrome P450 (CYP) upon IR. ROS scavenger N-acetyl-L-cysteine (NAC) and CYP inhibitor alizarin restored the viability of NUPR1-knockdown cells during IR. Mechanistically, the interaction between NUPR1 and aryl hydrocarbon receptor (AhR) promoted the degradation and decreased nuclear translation of AhR via the autophagy-lysosome pathway, followed by being incapable of CYP’s transcription. Furthermore, genetically and pharmacologically activating AhR abrogated the radioresistant role of NUPR1. Clinical data suggested that NUPR1 and AhR could serve as novel biomarkers for predicting the radiation response of HCC. Conclusions Our findings revealed the role of NUPR1 in regulating ROS homeostasis and oxidative stress via the AhR/CYP signal axis upon IR. Strategies targeting the NUPR1/AhR/CYP pathway may have important clinical applications for improving the radiotherapeutic efficacy of HCC.

ObjectiveTo explore the relationship between heart rate variability (HRV), the brain distribution of enlarged perivascular space (EPVS), and cognitive impairment in patients with EPVS.Materials and methodsThe clinical and imaging data of 199 patients with EPVS were retrospectively analyzed. EPVS load in the basal ganglia (BG) and centrum semiovale (CS) regions were assessed using the Potter’s method. Cognitive function was evaluated using the Montreal Cognitive Assessment Scale. A logistic regression model was used to analyze the relationship between HRV, the brain distribution of EPVS and cognitive function in patients with EPVS. A receiver operating characteristic curve was used to assess the predictive value of HRV for cognitive function in patients with EPVS.ResultsOf the 199 patients, 27 and 42 presented with severe BG-EPVS and cognitive impairment, respectively. Significant differences were observed in the root mean square of successive differences of normal-normal (NN) intervals for period of interest (rMSSD), the percentage of adjacent NN intervals greater than 50 ms (PNN50), and the ratio of low-frequency power (LF) to high-frequency power (HF) between the mild and severe BG-EPVS groups (P < 0.05). Patients who presented with and without cognitive impairment differed significantly in the standard deviation of NN intervals (SDNN), rMSSD, PNN50, total power, LF, and LF/HF (P < 0.05). rMSSD (odds ratio [OR] 0.871, 95% confidence interval [CI] 0.768–0.988) and LF/HF (OR 3.854, 95% CI 1.196–12.419) were independent influencing factors of BG-EPVS, and rMSSD (OR 0.936, 95% CI 0.898–0.976) was an independent influencing factor of cognitive impairment in patients with EPVS. The optimal cut-off point was 0.312, with an area under the curve of 0.795 (95% CI 0.719–0.872) for predicting cognitive impairment in patients with EPVS by rMSSD.ConclusionReduced HRV is involved in the pathophysiological mechanisms of the formation and development of BG-EPVS and is associated with cognitive impairment in patients with EPVS, independent of CS-EPVS. For patients with HRV changes but without autonomic nervous system symptoms, positive intervention may slow the occurrence or progression of EPVS and cognitive impairment in patients with EPVS.

On-chip multi-dimensional detection systems integrating pixelated polarization and spectral filter arrays are the latest trend in optical detection instruments, showing broad application potential for diagnostic medical imaging and remote sensing. However, thin-film or microstructure-based filter arrays typically have a trade-off between the detection dimension, optical efficiency, and spectral resolution. Here, we demonstrate novel on-chip integrated polarization spectral detection filter arrays consisting of metasurfaces and multilayer films. The metasurfaces with two nanopillars in one supercell are designed to modulate the Jones matrix for polarization selection. The angle of diffraction of the metasurfaces and the optical Fabry–Perot (FP) cavities determine the spectrum’s center wavelength. The polarization spectral filter arrays are placed on top of the CMOS sensor; each array corresponds to one pixel, resulting in high spectral resolution and optical efficiency in the selected polarization state. To verify the methodology, we designed nine-channel polarized spectral filter arrays in a wavelength range of 1350 nm to 1550 nm for transverse electric (TE) linear polarization. The array has a 10 nm balanced spectral resolution and average peak transmission efficiency of over 75%, which is maintained by utilizing lossless dielectric material. The proposed array can be fabricated using overlay e-beam lithography, and the process is CMOS-compatible. The proposed array enables broader applications of in situ on-chip polarization spectral detection with high efficiency and spectral resolution, as well as in vivo imaging systems.

Cardiac pathological hypertrophy is associated with undesirable epigenetic changes and causes maladaptive cardiac remodeling and heart failure, leading to high mortality rates. Specific drugs for the treatment of cardiac hypertrophy are still in urgent need. In the present study, a hydrogen-sulfide-releasing hybrid 13-E was designed and synthesized by appending p-hydroxythiobenzamide (TBZ), an H2S-releasing donor, to an analog of our previously discovered cardioprotective natural product XJP, 7,8-dihydroxy-3-methyl-isochromanone-4. This hybrid 13-E exhibited excellent H2S-generating ability and low cellular toxicity. The 13-E protected against cardiomyocyte hypertrophy In Vitro and reduced the induction of Anp and Bnp. More importantly, 13-E could reduce TAC-induced cardiac hypertrophy In Vivo, alleviate cardiac interstitial fibrosis and restore cardiac function. Unbiased transcriptomic analysis showed that 13-E regulated the AMPK signaling pathway and influenced fatty acid metabolic processes, which may be attributed to its cardioprotective activities.