Immune checkpoint (ICP) molecules expressed on tumor cells can suppress immune responses against tumors. ICP therapy promotes anti-tumor immune responses by targeting inhibitory and stimulatory pathways of immune cells like T cells and dendritic cells (DC). The investigation into the combination therapies through novel immune checkpoint inhibitors (ICIs) has been limited due to immune-related adverse events (irAEs), low response rate, and lack of optimal strategy for combinatorial cancer immunotherapy (IMT). Nanoparticles (NPs) have emerged as powerful tools to promote multidisciplinary cooperation. The feasibility and efficacy of targeted delivery of ICIs using NPs overcome the primary barrier, improve therapeutic efficacy, and provide a rationale for more clinical investigations. Likewise, NPs can conjugate or encapsulate ICIs, including antibodies, RNAs, and small molecule inhibitors. Therefore, combining the drug delivery system (DDS) with ICP therapy could provide a profitable immunotherapeutic strategy for cancer treatment. This article reviews the significant NPs with controlled DDS using current data from clinical and pre-clinical trials on mono- and combination IMT to overcome ICP therapeutic limitations. Graphical Abstract

Lithium has been a mainstay of therapy for patients with bipolar disorders for several decades. However, it may exert a variety of adverse effects that can affect patients’ compliance. Sexual and erectile dysfunction has been reported in several studies by patients who take lithium as monotherapy or combined with other psychotherapeutic agents. The exact mechanisms underlying such side effects of lithium are not completely understood. It seems that both central and peripheral mechanisms are involved in the lithium-related sexual dysfunction. Here, we had an overview of the epidemiology of lithium-related sexual and erectile dysfunction in previous clinical studies as well as possible pathologic pathways that could be involved in this adverse effect of lithium based on the previous preclinical studies. Understanding such mechanisms could potentially open a new avenue for therapies that can overcome lithium-related sexual dysfunction and improve patients’ adherence to the medication intake.

The Mela Rosa dei Monti Sibillini is an ancient apple variety cultivated by Romans in the foothills of the Sibillini Mountains, central Italy, showing potential as a source of nutraceuticals. The purpose of this study was to evaluate the protective effects of the hydroalcoholic extracts from the peel (APE) and pulp (APP) of this fruit in an animal model of transient global ischemia. Chemical constituents were analyzed by liquid chromatography–mass spectrometry (LC-DAD-MSⁿ) indicating several polyphenols such as B-type procyanidins, quercetin derivatives and hydroxycinnamic acids as the main bioactive components. Acute pre-treatment of extracts (30 mg/kg, i.p.) significantly decreased the brain levels of the pro-inflammatory cytokines IL-1β (p < 0.01) and TNF-α (p < 0.001 and p < 0.01 for APE and APP, respectively), the expression of caspase-3 (p < 0.01, For APE) and MDA (p < 0.05), a lipid peroxidation biomarker in rats. Both extracts restricted the pathological changes of the brain induced by ischemic stroke in hematoxylin and eosin assay. Moreover, they improved the scores of behavioral tests in grid-walking and modified neurological severity scores (mNSS) tests. In conclusion, these results proved this ancient Italian apple is a source of nutraceuticals able to protect/prevent damage from brain ischemia.