The Prognostic Significance of Pontine-White Matter Score in Primary Central Nervous System Lymphoma Patients.

BACKGROUND: Limited data exist on the significance of PET imaging and quantitative PET parameters in primary central nervous system (CNS) lymphoma due to its relative rarity. This study was conducted to investigate the prognostic value of a novel internal standardization indicator, the pontine-white matter (PW) score, in primary CNS lymphoma patients undergoing post-treatment 18F-FDG PET/CT and PET/MR imaging. METHODS: From January 2014 to December 2022, eligible patients with primary CNS lymphoma who underwent post-treatment PET imaging were enrolled. Using the FDG uptake of the pons and white matter as an internal reference, the PW score was graded based on the metabolism of the post-therapeutic lesion for each patient, and its associations with patients' prognosis were investigated. RESULTS: In total, 41 patients with post-treatment PET/CT and 49 patients with post-treatment PET/MR imaging were enrolled. ROC curve analysis indicated that the PW score possessed robust discriminative ability in distinguishing patients with worse outcomes. Furthermore, a higher PW score was significantly correlated with and identified as an independent prognostic indicator for, worse prognosis in both the PET/CT and PET/MR cohorts. CONCLUSION: The study demonstrated that the PW score was an effective prognostic indicator for identifying post-treatment primary CNS lymphoma patients with worse outcomes.

Biointerface-Engineered Hybrid Nanovesicles for Targeted Reprogramming of Tumor Microenvironment.

The tumor microenvironment (TME) of typical tumor types such as triple-negative breast cancer is featured by hypoxia and immunosuppression with abundant tumor-associated macrophages (TAMs), which also emerge as potential therapeutic targets for antitumor therapy. M1-like macrophage-derived exosomes (M1-Exos) have emerged as a promising tumor therapeutic candidate for their tumor-targeting and macrophage-polarization capabilities. However, the limited drug-loading efficiency and stability of M1-Exos have hindered their effectiveness in antitumor applications. Here, a hybrid nanovesicle is developed by integrating M1-Exos with AS1411 aptamer-conjugated liposomes (AApt-Lips), termed M1E/AALs. The obtained M1E/AALs are loaded with perfluorotributylamine (PFTBA) and IR780, as P-I, to construct P-I@M1E/AALs for reprogramming TME by alleviating tumor hypoxia and engineering TAMs. P-I@M1E/AAL-mediated tumor therapy enhances the in situ generation of reactive oxygen species, repolarizes TAMs toward an antitumor phenotype, and promotes the infiltration of T lymphocytes. The synergistic antitumor therapy based on P-I@M1E/AALs significantly suppresses tumor growth and prolongs the survival of 4T1-tumor-bearing mice. By integrating multiple treatment modalities, P-I@M1E/AAL nanoplatform demonstrates a promising therapeutic approach for overcoming hypoxic and immunosuppressive TME by targeted TAM reprogramming and enhanced tumor photodynamic immunotherapy. This study highlights an innovative TAM-engineering hybrid nanovesicle platform for the treatment of tumors characterized by hypoxic and immunosuppressive TME.

Resolvin D1 delivery to lesional macrophages using antioxidative black phosphorus nanosheets for atherosclerosis treatment.

The buildup of plaques in atherosclerosis leads to cardiovascular events, with chronic unresolved inflammation and overproduction of reactive oxygen species (ROS) being major drivers of plaque progression. Nanotherapeutics that can resolve inflammation and scavenge ROS have the potential to treat atherosclerosis. Here we demonstrate the potential of black phosphorus nanosheets (BPNSs) as a therapeutic agent for the treatment of atherosclerosis. BPNSs can effectively scavenge a broad spectrum of ROS and suppress atherosclerosis-associated pro-inflammatory cytokine production in lesional macrophages. We also demonstrate ROS-responsive, targeted-peptide-modified BPNS-based carriers for the delivery of resolvin D1 (an inflammation-resolving lipid mediator) to lesional macrophages, which further boosts the anti-atherosclerotic efficacy. The targeted nanotherapeutics not only reduce plaque areas but also substantially improve plaque stability in high-fat-diet-fed apolipoprotein E-deficient mice. This study presents a therapeutic strategy against atherosclerosis, and highlights the potential of BPNS-based therapeutics to treat other inflammatory diseases.

Hemodynamics of ventricular-arterial coupling under enhanced external counterpulsation: An optimized dual-source lumped parameter model.

BACKGROUND AND OBJECTIVE: Enhanced external counterpulsation (EECP) is a mechanically assisted circulation technique widely used in the rehabilitation and management of ischemic cardiovascular diseases. It contributes to cardiovascular functions by regulating the afterload of ventricle to improve hemodynamic effects, including increased diastolic blood pressure at aortic root, increased cardiac output and enhanced blood perfusion to multiple organs including coronary circulation. However, the effects of EECP on the coupling of the ventricle and the arterial system, termed ventricular-arterial coupling (VAC), remain elusive. We aimed to investigate the acute effect of EECP on the dynamic interaction between the left ventricle and its afterload of the arterial system from the perspective of ventricular output work. METHODS: A neural network assisted optimization algorithm was proposed to identify the ordinary differential equation (ODE) relation between aortic root blood pressure and flow rate. Based on the optimized order of ODE, a lumped parameter model (LPM) under EECP was developed taking into consideration of the simultaneous action of cardiac and EECP pressure sources. The ventricular output work, in terms of aortic pressure and flow rate cooperated with the LPM, was used to characterize the VAC of ventricle and its afterload. The VAC subjected to the principle of minimal ventricular output work was validated by solving the Euler-Poisson equation of cost function, ultimately determining the waveforms of aortic pressure and flow rate. RESULTS: A third-order ODE can precisely describe the hemodynamic relationship between aortic pressure and flow rate. An optimized dual-source LPM with three energy-storage elements has been constructed, showing the potential in probing VAC under EECP. The LPM simulation results demonstrated that the VAC in terms of aortic pressure and flow rate yielded to the minimal ventricular output work under different EECP pressures. CONCLUSIONS: The ventricular-arterial coupling under EECP is subjected to the minimal ventricular output work, which can serve as a criterion for determining aortic pressure and flow rate. This study provides insight for the understanding of VAC and has the potential in characterizing the performance of the ventricular and arterial system under EECP.

Macrophage-modulating nanomedicine for cancer immunotherapy.

Tumor-associated macrophages (TAMs) play crucial roles in the immunosuppressive solid tumor microenvironment (TME). Despite their tumor-promoting functions, TAMs can also be therapeutically modulated to exhibit tumor-killing properties, making them attractive targets for tumor immunotherapy. This review highlights the recent advances in nanomedicine-based strategies centered around macrophages for enhanced cancer immunotherapy. Emerging nanomedicine-based strategies to modulate TAMs in cancer treatment include repolarization of the TAM phenotype, inhibition of monocyte recruitment, depletion of TAMs, and blockage of immune checkpoints. These strategies have shown great promise in significantly improving the efficacy of cancer immunotherapy. Moreover, macrophage-inspired drug delivery systems have demonstrated significant promise in inducing immunotherapeutic effects and enhancing therapeutic efficacy by facilitating evasion from the reticuloendothelial system and promoting accumulation at the tumor site. Finally, we also discuss the challenges and propose future opportunities associated with macrophage-modulating nanomedicine to enhance cancer immunotherapy.

Safe Induction of Acute Inflammation with Enhanced Antitumor Immunity by Hydrogel-Mediated Outer Membrane Vesicle Delivery.

Acute inflammation has the potential for the recruitment of immune cells, inhibiting tumor angiogenesis, metastasis, and drug resistance thereby overcoming the tumor immunosuppressive microenvironment caused by chronic inflammation. Here, an acute inflammation inducer using bacteria outer membrane vesicles (OMVs) loaded in thermal-sensitive hydrogel (named OMVs-gel) for localized and controlled release of OMVs in tumor sites is proposed. OMVs trigger neutrophil recruitment and amplify acute inflammation inside tumor tissues. The hydrogel ensures drastic inflammation is confined within the tumor, addressing biosafety concerns that the direct administration of free OMVs may cause fatal effects. This strategy eradicated solid tumors safely and rapidly. The study further elucidates one of the possible immune mechanisms of OMVs-gel therapy, which involves the assembly of antitumor neutrophils and elastase release for selective tumor killing. Additionally, tumor vascular destruction induced by OMVs-gel results in tumor darkening, allowing for combinational photothermal therapy. The findings suggest that the use of OMVs-gel can safely induce acute inflammation and enhance antitumor immunity, representing a promising strategy to promote acute inflammation application in tumor immunotherapy.

Chemically Modified Platforms for Better RNA Therapeutics.

RNA-based therapies have catalyzed a revolutionary transformation in the biomedical landscape, offering unprecedented potential in disease prevention and treatment. However, despite their remarkable achievements, these therapies encounter substantial challenges including low stability, susceptibility to degradation by nucleases, and a prominent negative charge, thereby hindering further development. Chemically modified platforms have emerged as a strategic innovation, focusing on precise alterations either on the RNA moieties or their associated delivery vectors. This comprehensive review delves into these platforms, underscoring their significance in augmenting the performance and translational prospects of RNA-based therapeutics. It encompasses an in-depth analysis of various chemically modified delivery platforms that have been instrumental in propelling RNA therapeutics toward clinical utility. Moreover, the review scrutinizes the rationale behind diverse chemical modification techniques aiming at optimizing the therapeutic efficacy of RNA molecules, thereby facilitating robust disease management. Recent empirical studies corroborating the efficacy enhancement of RNA therapeutics through chemical modifications are highlighted. Conclusively, we offer profound insights into the transformative impact of chemical modifications on RNA drugs and delineates prospective trajectories for their future development and clinical integration.

Biomimetic nanodecoys deliver cholesterol-modified heteroduplex oligonucleotide to target dopaminergic neurons for the treatment of Parkinson's disease.

Parkinson's disease (PD) is the second most common neurodegenerative disorder characterized by the accumulation of α-synuclein (α-syn) aggregates called Lewy bodies leading to the gradual loss of dopaminergic (DA) neurons in the substantia nigra. Although α-syn expression can be attenuated by antisense oligonucleotides (ASOs) and heteroduplex oligonucleotide (HDO) by intracerebroventricular (ICV) injection, the challenge to peripheral targeted delivery of oligonucleotide safely and effectively into DA neurons remains unresolved. Here, we designed a new DNA/DNA double-stranded (complementary DNA, coDNA) molecule with cholesterol conjugation (Chol-HDO (coDNA)) based on an α-syn-ASO sequence and evaluated its silence efficiency. Further, Chol-HDO@LMNPs, Chol-HDO-loaded, cerebrovascular endothelial cell membrane with DSPE-PEG2000-levodopa modification (L-DOPA-CECm)-coated nanoparticles (NPs), were developed for the targeted treatment of PD by tail intravenous injection. CECm facilitated the blood-brain barrier (BBB) penetration of NPs, together with cholesterol escaped from reticuloendothelial system uptake, as well as L-DOPA was decarboxylated into dopamine which promoted the NPs toward the PD site for DA neuron regeneration. The behavioral tests demonstrated that the nanodecoys improved the efficacy of HDO on PD mice. These findings provide insights into the development of biomimetic nanodecoys loading HDO for precise therapy of PD. STATEMENT OF SIGNIFICANCE: The accumulation of α-synuclein (α-syn) aggregates is a hallmark of PD. Our previous study designed a specific antisense oligonucleotide (ASO) targeting human SNCA, but the traumatic intracerebroventricular (ICV) is not conducive to clinical application. Here, we further optimize the ASO by creating a DNA/DNA double-stranded molecule with cholesterol-conjugated, named Chol-HDO (coDNA), and develop a DA-targeted biomimetic nanodecoy Chol-HDO@LMNPs by engineering cerebrovascular endothelial cells membranes (CECm) with DSPE-PEG2000 and L-DOPA. The in vivo results demonstrated that tail vein injection of Chol-HDO@LMNPs could target DA neurons in the brain and ameliorate motor deficits in a PD mouse model. This investigation provides a promising peripheral delivery platform of L-DOPA-CECm nanodecoy loaded with a new Chol-HDO (coDNA) targeting DA neurons in PD therapy.