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A dose threshold of one trillion nanoparticles in mice has been discovered and is shown to be crucial for overwhelming the nanoparticle uptake kinetics of liver Kupffer cells and for ensuring efficient nanoparticle delivery into solid tumours upon intravenous administration.

Following its discovery more than 30 years ago, the enhanced permeability and retention (EPR) effect has become the guiding principle for cancer nanomedicine development. Over the years, the tumor-targeted drug delivery field has made significant progress, as evidenced by the approval of several nanomedicinal anticancer drugs. Recently, however, the existence and the extent of the EPR effect - particularly in patients - have become the focus of intense debate. This is partially due to the disbalance between the huge number of preclinical cancer nanomedicine papers and relatively small number of cancer nanomedicine drug products reaching the market. To move the field forward, we have to improve our understanding of the EPR effect, of its cancer type-specific pathophysiology, of nanomedicine interactions with the heterogeneous tumor microenvironment, of nanomedicine behavior in the body, and of translational aspects that specifically complicate nanomedicinal drug development. In this virtual special issue, 24 research articles and reviews discussing different aspects of the EPR effect and cancer nanomedicine are collected, together providing a comprehensive and complete overview of the current state-of-the-art and future directions in tumor-targeted drug delivery.

Gold nanoparticles display unique physicochemical features, which can be useful for therapeutic purposes. After two decades of preclinical progress, gold nanoconstructs are slowly but steadily transitioning into clinical trials. Although initially thought to be “magic golden bullets” that could be used to treat a wide range of diseases, current consensus has moved toward a more realistic approach, where gold nanoformulations are being investigated to treat specific disorders. These therapeutic applications are dictated by the pharmacokinetics and biodistribution profiles of gold nanoparticles. Here, we analyze the current clinical landscape of therapeutic gold nanoconstructs, discuss the shared characteristics that allowed for their transition from bench to bedside, and examine existing hurdles that need to be overcome before they can be approved for clinical use. Graphical Abstract

Nano-formulating dexamethasone, and administering it via intravenous injection or inhalation, may help to improve anti-COVID-19 treatment efficacy by targeting the potent corticosteroid drug to hyper-activated immune cells, by potentiating its anti-oedema activity and by exploiting its anti-fibrotic effects.

Super-resolution imaging methods promote tissue characterization beyond the spatial resolution limits of the devices and bridge the gap between histopathological analysis and non-invasive imaging. Here, we introduce motion model ultrasound localization microscopy (mULM) as an easily applicable and robust new tool to morphologically and functionally characterize fine vascular networks in tumors at super-resolution. In tumor-bearing mice and for the first time in patients, we demonstrate that within less than 1 min scan time mULM can be realized using conventional preclinical and clinical ultrasound devices. In this context, next to highly detailed images of tumor microvascularization and the reliable quantification of relative blood volume and perfusion, mULM provides multiple new functional and morphological parameters that discriminate tumors with different vascular phenotypes. Furthermore, our initial patient data indicate that mULM can be applied in a clinical ultrasound setting opening avenues for the multiparametric characterization of tumors and the assessment of therapy response. The vascular structure of tumors impacts diagnosis, prognosis and drug response; however, imaging methods to analyse this important feature have been hindered by spatial resolution limitations. Here the authors present a tool called motion model ultrasound localization microscopy to morphologically and functionally characterize fine vascular networks in tumors at super-resolution.

In nephrology, differential diagnosis or assessment of disease activity largely relies on the analysis of glomerular filtration rate, urinary sediment, proteinuria and tissue obtained through invasive kidney biopsies. However, currently available non-invasive functional parameters, and most serum and urine biomarkers, cannot capture intrarenal molecular disease processes specifically. Moreover, although histopathological analyses of kidney biopsy samples enable the visualization of pathological morphological and molecular alterations, they only provide information about a small part of the kidney and do not allow longitudinal monitoring. These limitations not only hinder understanding of the dynamics of specific disease processes in the kidney, but also limit the targeting of treatments to active phases of disease and the development of novel targeted therapies. Molecular imaging enables non-invasive and quantitative assessment of physiological or pathological processes by combining imaging technologies with specific molecular probes. Here, we discuss current preclinical and clinical molecular imaging approaches in nephrology. Non-invasive visualization of the kidneys through molecular imaging can be used to detect and longitudinally monitor disease activity and can therefore provide companion diagnostics to guide clinical trials, as well as the safe and effective use of drugs.In vivo non-invasive molecular imaging techniques have potential to improve clinical research and practices in nephrology. Here, the authors discuss the benefits and challenges of preclinical and clinical applications of molecular imaging to acute kidney injury and chronic kidney disease, transplantation and kidney cancer.

Immunotherapy is rapidly maturing towards extensive clinical use. However, it does not work well in large patient populations because of an immunosuppressed microenvironment and limited reinvigoration of antitumor immunity. The tumor microenvironment is a complex milieu in which the principles of physiology and anatomy are defied and which is considered an immune-privileged site promoting T cell exhaustion. Tremendous research interest exists in developing nanoparticle-based approaches to modulate antitumor immune responses. The increasing use of immunotherapies in the clinic requires robust programming of immune cells to boost antitumor immunity. This review summarizes recent advances in the engineering of nanoparticles for improved anticancer immunotherapy. It discusses emerging nanoparticle-based approaches for the modulation of tumor cells and immune cells, such as dendritic cells, T cells and tumor-associated macrophages, with the intention to overcome challenges currently faced in the clinic. Furthermore, this review describes potentially curative combination therapeutic approaches to provoke effective tumor antigen-specific immune responses. We foresee a future in which improvement in patient's surveillance will become a mainstream practice.

Nanomedicines can be used for a variety of cancer therapies including tumor-targeted drug delivery, hyperthermia, and photodynamic therapy. Poly (lactic-co-glycolic acid) (PLGA)-based materials are frequently used in such setups. This review article gives an overview of the properties of previously reported PLGA nanoparticles (NPs), their behavior in biological systems, and their use for cancer therapy. Strategies are emphasized to target PLGA NPs to the tumor site passively and actively. Furthermore, combination therapies are introduced that enhance the accumulation of NPs and, thereby, their therapeutic efficacy. In this context, the huge number of reports on PLGA NPs used as drug delivery systems in cancer treatment highlight the potential of PLGA NPs as drug carriers for cancer therapeutics and encourage further translational research.

Nanomedicines have created a paradigm shift in healthcare. Yet fundamental barriers still exist that prevent or delay the clinical translation of nanomedicines. Critical hurdles inhibiting clinical success include poor understanding of nanomedicines’ physicochemical properties, limited exposure in the cell or tissue of interest, poor reproducibility of preclinical outcomes in clinical trials, and biocompatibility concerns. Barriers that delay translation include industrial scale-up or scale-down and good manufacturing practices, funding and navigating the regulatory environment. Here we propose the DELIVER framework comprising the core principles to be realized during preclinical development to promote clinical investigation of nanomedicines. The proposed framework comes with design, experimental, manufacturing, preclinical, clinical, regulatory and business considerations, which we recommend investigators to carefully review during early-stage nanomedicine design and development to mitigate risk and enable timely clinical success. By reducing development time and clinical trial failure, it is envisaged that this framework will help accelerate the clinical translation and maximize the impact of nanomedicines. The authors propose a framework to be followed during preclinical investigation of nanomedicines to increase their translatability potential.

Objectives In chronic liver injury, angiogenesis, the formation of new blood vessels from pre-existing ones, may contribute to progressive hepatic fibrosis and to development of hepatocellular carcinoma. Although hypoxia-induced expression of vascular endothelial growth factor (VEGF) occurs in advanced fibrosis, we hypothesised that inflammation may endorse hepatic angiogenesis already at early stages of fibrosis. Design Angiogenesis in livers of c57BL/6 mice upon carbon tetrachloride- or bile duct ligation-induced chronic hepatic injury was non-invasively monitored using in vivo contrast-enhanced micro computed tomography (µCT) and ex vivo anatomical µCT after hepatic Microfil perfusion. Functional contributions of monocyte-derived macrophage subsets for angiogenesis were explored by pharmacological inhibition of CCL2 using the Spiegelmer mNOX-E36. Results Contrast-enhanced in vivo µCT imaging allowed non-invasive monitoring of the close correlation of angiogenesis, reflected by functional hepatic blood vessel expansion, with experimental fibrosis progression. On a cellular level, inflammatory monocyte-derived macrophages massively accumulated in injured livers, colocalised with newly formed vessels in portal tracts and exhibited pro-angiogenic gene profiles including upregulated VEGF and MMP9. Functional in vivo and anatomical ex vivo µCT analyses demonstrated that inhibition of monocyte infiltration by targeting the chemokine CCL2 prevented fibrosis-associated angiogenesis, but not fibrosis progression. Monocyte-derived macrophages primarily fostered sprouting angiogenesis within the portal vein tract. Portal vein diameter as a measure of portal hypertension depended on fibrosis, but not on angiogenesis. Conclusions Inflammation-associated angiogenesis is promoted by CCL2-dependent monocytes during fibrosis progression. Innovative in vivo µCT methodology can accurately monitor angiogenesis and antiangiogenic therapy effects in experimental liver fibrosis.