Nanoparticles (NPs) are versatile candidates for nanomedical applications due to their unique physicochemical properties. However, their clinical applicability is hindered by their undesirable recognition by the immune system and the consequent immunotoxicity, as well as their rapid clearance in vivo. After injection, NPs are usually covered with layers of proteins, called protein coronas (PCs), which alter their identity, biodistribution, half-life, and efficacy. Therefore, the characterization of the PC is for in predicting the fate of NPs in vivo. The aim of this review was to summarize the state of the art regarding the intrinsic factors closely related to the NP structure, and extrinsic factors that govern PC formation in vitro. In addition, well-known opsonins, including complement, immunoglobulins, fibrinogen, and dysopsonins, such as histidine-rich glycoprotein, apolipoproteins, and albumin, are described in relation to their role in NP detection by immune cells. Particular emphasis is placed on their role in mediating the interaction of NPs with innate and adaptive immune cells. Finally, strategies to reduce PC formation are discussed in detail.

Inflammation plays a crucial role in cancer progression, but the relevance of the inflammasome remains unclear. Alu RNA was the first endogenous nucleic acid shown to activate the NLRP3 (nucleotide-binding domain leucine-rich repeat containing 3) inflammasome. Here, we showed that Alu RNA can induce epithelial-to-mesenchymal transition (EMT) through NLRP3 inflammasome activation and IL-1β release in colorectal cancer (CRC) cells. Alu RNA is stored, transported and transferred to CRC cells by exosomes. Exosomal Alu RNA promotes tumorigenesis by inducing invasion, metastasis and EMT via NLRP3 inflammasome activation. Consistent with these data, we found that significantly increased Alu RNA expression correlates with the induction of NLRP3 priming in human CRC patients. Furthermore, the level of Alu RNA in circulating exosomes correlates with CRC progression in a preclinical model. These findings reveal the direct involvement of Alu RNA in cancer pathogenesis, and its presence in CRC cell-derived exosomes could be used as a noninvasive diagnostic biomarker.

Purpose: Recruitment and activation of inflammatory cells, such as retinal microglia/macrophages, in the subretinal space contribute significantly to the pathogenesis of age-related macular degeneration (AMD). This study aims to explore the functional role of vascular endothelial growth factor (VEGF-A), placental growth factor (PlGF) and VEGF-A/PlGF heterodimer in immune homeostasis and activation during pathological laser-induced choroidal neovascularization (CNV). Methods: To investigate these roles, we utilized the PlGF-DE knockin (KI) mouse model, which is the full functional knockout (KO) of PlGF. In this model, mice express a variant of PlGF, named PlGF-DE, that is unable to bind and activate VEGFR-1 but can still form heterodimer with VEGF-A. Results: Our findings demonstrate that, although there is no difference in healthy conditions, PlGF-DE-KI mice exhibit decreased microglia reactivity and reduced recruitment of both microglia and monocyte-macrophages, compared to wild-type mice during laser-induced CNV. This impairment is associated with a reduction in VEGF receptor 1 (VEGFR-1) phosphorylation in the retinae of PlGF-DE-KI mice compared to C57Bl6/J mice. Corroborating these data, intravitreal delivery of PlGF or VEGF-A/PlGF heterodimer in PlGF-DE-KI mice rescued the immune cell response at the early phase of CNV compared to VEGF-A delivery. Conclusions: In summary, our study suggests that targeting PlGF and the VEGF-A/PlGF heterodimer, thereby preventing VEGFR-1 activation, could represent a potential therapeutic approach for the management of inflammatory processes in diseases such as AMD.

Prolyl 3-hydroxylase 2 (P3H2) is a key enzyme involved in the architecture of the extracellular matrix (ECM). While previously shown to be regulated by VEGF-A and to play a role in angiogenesis, its function in cancer remains ambiguous. While characterized as a tumor suppressor, its precise function in colorectal cancer (CRC) progression is poorly defined. Bioinformatic analysis and patient data reveal that P3H2 transcript levels are significantly reduced in colon adenocarcinoma tissues, showing a progressive decline in metastatic lesions. Furthermore, VEGF-A exposure upregulates P3H2 transcripts in the HCT116 CRC cell line. To investigate its impact in CRC, we generated a stable HCT116 clone overexpressing P3H2. In vitro studies demonstrated that while P3H2 overexpression inhibited anchorage-independent growth, it significantly enhanced cellular invasion without altering cell proliferation. In vivo, however, P3H2-overexpressing tumors exhibited accelerated tumor growth and a statistically significant increase in lung metastases. P3H2 overexpression remodeled the tumor microenvironment (TME) by modifying its main substrate, Collagen IV, resulting in the induction of increased vessels density. Our study repositions P3H2 as a dynamic enzymatic switch within the TME. This work identifies P3H2-driven ECM remodeling as a promising therapeutic axis in advanced CRC, with particular relevance for combination strategies targeting angiogenesis.