In cancer therapy and imaging, the systemic passive delivery of particulate systems has relied on the enhanced permeability and retention (EPR) effect: sufficiently small particles can cross the endothelial fenestrations and accumulate in the tumor parenchyma. The vast majority of man-made particulates exhibit a spherical shape as a result of surface energy minimization during their synthesis. The advent of phage display libraries, which are revealing the extraordinary molecular diversity of endothelial cells, and the development of processes for fabricating particles with shapes other than spherical are opening the path to new design solutions for systemically administered targeted particulates. In this paper, the role of particle geometry (i.e., size and shape) is discussed at the tissue and cellular scales. Emphasis is placed on how the synergistic effect of particle geometry and molecular targeting can enhance the specificity of delivery. The intravascular delivery process has been broken into three events: margination, firm adhesion and control of internalization. Predictions from mathematical models and observations from in-vitro experiments were used to show the relevance of particle geometry in systemic delivery. Rational design of particulate systems should consider, beside the physico-chemical properties of the surface coatings, geometrical features as size and shape. The integration of mathematical modeling with in-vitro and in-vivo testing provides the tools for establishing a rational design of nanoparticles.

Ionizable lipid nanoparticles (LNPs) are the most clinically advanced nano‐delivery system for therapeutic nucleic acids. The great effort put in the development of ionizable lipids with increased in vivo potency brought LNPs from the laboratory benches to the FDA approval of patisiran in 2018 and to the ongoing clinical trials for mRNA‐based vaccines against SARS‐CoV‐2. Despite these success stories, several challenges remain in RNA delivery, including what is known as “endosomal escape”. Reaching the cytosol is mandatory for unleashing the therapeutic activity of RNA molecules, as their accumulation in other intracellular compartments would simply result in efficacy loss. In LNPs, the ability of ionizable lipids to form destabilizing non‐bilayer structures at acidic pH is recognized as the key for endosomal escape and RNA cytosolic delivery. This is motivating a surge in studies aiming at designing novel ionizable lipids with improved biodegradation and safety profiles. In this work, we describe the journey of RNA‐loaded LNPs across multiple intracellular barriers, from the extracellular space to the cytosol. In silico molecular dynamics modeling, in vitro high‐resolution microscopy analyses and in vivo imaging data are systematically reviewed to distill out the regulating mechanisms underlying the endosomal escape of RNA. Lastly, a comparison with strategies employed by enveloped viruses to deliver their genetic material into cells is also presented. The combination of a multidisciplinary analytical toolkit for endosomal escape quantification and a nature‐inspired design could foster the development of future LNPs with improved cytosolic delivery of nucleic acids.

Magnetic resonance imaging contrast agents are currently designed by modifying their structural and physiochemical properties to improve relaxivity and to enhance image contrast. Here, we show a general method for increasing relaxivity by confining contrast agents inside the nanoporous structure of silicon particles. Magnevist, gadofullerenes and gadonanotubes were loaded inside the pores of quasi-hemispherical and discoidal particles. For all combinations of nanoconstructs, a boost in longitudinal proton relaxivity r₁ was observed: Magnevist, r₁ ≈ 14 mM⁻¹ s⁻¹/Gd³⁺ ion (∼8.15 × 10⁺⁷ mM⁻¹ s⁻¹/construct); gadofullerenes, r₁ ≈ 200 mM⁻¹ s⁻¹/Gd³⁺ ion (∼7 × 10⁺⁹ mM⁻¹ s⁻¹/construct); gadonanotubes, r₁ ≈ 150 mM⁻¹ s⁻¹/Gd³⁺ ion (∼2 × 10⁺⁹ mM⁻¹ s⁻¹/construct). These relaxivity values are about 4 to 50 times larger than those of clinically available gadolinium-based agents (∼4 mM⁻¹ s⁻¹/Gd³⁺ ion). The enhancement in contrast is attributed to the geometrical confinement of the agents, which influences the paramagnetic behaviour of the Gd³⁺ ions. Thus, nanoscale confinement offers a new and general strategy for enhancing the contrast of gadolinium-based contrast agents.