Cancer extracellular vesicles (EVs) shuttle at distance and fertilize pre-metastatic niches facilitating subsequent seeding by tumor cells. However, the link between EV secretion mechanisms and their capacity to form pre-metastatic niches remains obscure. Using mouse models, we show that GTPases of the Ral family control, through the phospholipase D1, multi-vesicular bodies homeostasis and tune the biogenesis and secretion of pro-metastatic EVs. Importantly, EVs from RalA or RalB depleted cells have limited organotropic capacities in vivoand are less efficient in promoting metastasis. RalA and RalB reduce the EV levels of the adhesion molecule MCAM/CD146, which favors EV-mediated metastasis by allowing EVs targeting to the lungs. Finally, RalA, RalB, and MCAM/CD146, are factors of poor prognosis in breast cancer patients. Altogether, our study identifies RalGTPases as central molecules linking the mechanisms of EVs secretion and cargo loading to their capacity to disseminate and induce pre-metastatic niches in a CD146-dependent manner.

Tumor‐targeted antibody (mAb)/fragment‐conjugated nanoparticles (NPs) represent an innovative strategy for improving the local delivery of small molecules. However, the physicochemical properties of full mAb–NPs and fragment–NPs—that is, NP material, size, charge, as well as the targeting antibody moiety, and the linker conjugation strategies—remain to be optimized to achieve an efficient tumor targeting. A meta‐analysis of 161 peer‐reviewed studies is presented, which describes the use of tumor‐targeted mAb–NPs and fragment−NPs from 2009 to 2021. The use of these targeted NPs is confirmed to result in significantly greater tumor uptake of NPs than that of naked NPs (7.9 ± 1.9% ID g−1 versus 3.2 ± 0.6% ID g−1, respectively). The study further demonstrates that for lipidic NPs, fragment–NPs provide a significantly higher tumor uptake than full mAb–NPs. In parallel, for both polymeric and organic/inorganic NPs, full mAb–NPs yield a significant higher tumor uptake than fragment–NPs. In addition, for both lipidic and polymeric NPs, the tumor uptake is improved with the smallest sizes of the conjugates. Finally, the pharmacokinetics of the conjugates are demonstrated to be driven by the NPs and not by the antibody moieties, independently of using full mAb–NPs or fragment–NPs, confirming the importance of optimizing the NP design to improve the tumor uptake.

Current clinical imaging modalities for the sensitive and specific detection of multiple myeloma (MM) rely on nonspecific imaging contrast agents based on gadolinium chelates for magnetic resonance imaging (MRI) or for 18 F-FDG-directed and combined positron emission tomography (PET) and computed tomography (CT) scans. These tracers are not, however, able to detect minute plasma cell populations in the tumor niche, leading to false negative results. Here, a novel PET-based anti-BCMA nanoplatform labeled with 64 Cu is developed to improve the monitoring of these cells in both the spine and femur and to compare its sensitivity and specificity to more conventional immunoPET ( 64 Cu labeled anti-BCMA antibody) and passively targeted PET radiotracers ( 64 CuCl 2 and 18 F-FDG). This proof-of-concept preclinical study confirmed that by conjugating up to four times more radioisotopes per antibody with the immuno-nanoPET platform, an improvement in the sensitivity and in the specificity of PET to detect tumor cells in an orthotopic model of MM is observed when compared to the traditional immunoPET approach. It is anticipated that when combined with tumor biopsy, this immuno-nanoPET platform may improve the management of patients with MM.

Considerable progress has been made in the development and understanding of immunotherapy, notably with the emergence of novel chimeric antigen receptor T cells (CAR-T) which changed the perception of personalized therapy. However, cell-based immunotherapy not only lacks therapeutic efficiency in various solid cancers but also raises concerns related to important side effects. The convergence of immunotherapy and nanomedicine is timely as nanoparticles can now be easily conjugated to various antibodies and peptides enabling outstanding abilities to target specific cell populations in vivo. Here, the state of the art of immunonanotherapy that activates the immune system in vivo, by acting either as vaccines or as tumor microenvironment (TME) activators is described. Then, the development of ex vivo immune-cell surface labeling strategies is discussed to exploit immune cells as trojan horses and thereby improving the delivery of the therapeutics in the TME. Such a strategy is likely to considerably amplify the efficacy of immunotherapy.