Self-assembling molecular drugs combine the easy preparation typical of small-molecule chemotherapy and the tumour-targeting properties of drug–nanoparticle conjugates. However, they require a supramolecular interaction that survives the complex environment of a living animal. Here we report that the metallophilic interaction between cyclometalated palladium complexes generates supramolecular nanostructures in living mice that have a long circulation time (over 12 h) and efficient tumour accumulation rate (up to 10.2% of the injected dose per gram) in a skin melanoma tumour model. Green light activation leads to efficient tumour destruction due to the type I photodynamic effect generated by the self-assembled palladium complexes, as demonstrated in vitro by an up to 96-fold cytotoxicity increase upon irradiation. This work demonstrates that metallophilic interactions are well suited to generating stable supramolecular nanotherapeutics in vivo with exceptional tumour-targeting properties.

Surface charge plays a fundamental role in determining the fate of a nanoparticle, and any encapsulated contents, in vivo. Herein, we describe, and visualise in real time, light-triggered switching of liposome surface charge, from neutral to cationic, in situ and in vivo (embryonic zebrafish). Prior to light activation, intravenously administered liposomes, composed of just two lipid reagents, freely circulate and successfully evade innate immune cells present in the fish. Upon in situ irradiation and surface charge switching, however, liposomes rapidly adsorb to, and are taken up by, endothelial cells and/or are phagocytosed by blood resident macrophages. Coupling complete external control of nanoparticle targeting together with the intracellular delivery of encapsulated (and membrane impermeable) cargos, these compositionally simple liposomes are proof that advanced nanoparticle function in vivo does not require increased design complexity but rather a thorough understanding of the fundamental nano-bio interactions involved.

A simple di(thioamido)carbazole 1 serves as a potent multispecific transporter for various biologically relevant oxyanions, such as drugs, metabolites and model organic phosphate. The transport kinetics of a wide range of oxyanions can be easily quantified by a modified lucigenin assay in both large and giant unilamellar vesicles.

Plasma lipid transport and metabolism are essential to ensure correct cellular function throughout the body. Dynamically regulated in time and space, the well‐characterized mechanisms underpinning plasma lipid transport and metabolism offers an enticing, but as yet underexplored, rationale to design synthetic lipid nanoparticles with inherent cell/tissue selectivity. Herein, a systemically administered liposome formulation, composed of just two lipids, that is capable of hijacking a triglyceride lipase‐mediated lipid transport pathway resulting in liposome recognition and uptake within specific endothelial cell subsets is described. In the absence of targeting ligands, liposome‐lipase interactions are mediated by a unique, phase‐separated (“parachute”) liposome morphology. Within the embryonic zebrafish, selective liposome accumulation is observed at the developing blood‐brain barrier. In mice, extensive liposome accumulation within the liver and spleen – which is reduced, but not eliminated, following small molecule lipase inhibition – supports a role for endothelial lipase but highlights these liposomes are also subject to significant “off‐target” by reticuloendothelial system organs. Overall, these compositionally simplistic liposomes offer new insights into the discovery and design of lipid‐based nanoparticles that can exploit endogenous lipid transport and metabolism pathways to achieve cell selective targeting in vivo.

In the present study, liposomes consisting of DSPC and DOaG molecular analogues were assessed for their phase-separated morphology (cryoTEM), stability (DLS) and in vivo biodistribution (targeting the brain endothelial cells of zebrafish embryos).

Glucocorticoids (GCs) are effective anti-inflammatory drugs, but their clinical use is limited by their side effects. Using liposomes to target GCs to inflammatory sites is a promising approach to improve their therapeutic ratio. We used zebrafish embryos to visualize the biodistribution of liposomes and to determine the anti-inflammatory and adverse effects of the GC prednisolone phosphate (PLP) encapsulated in these liposomes. Our results showed that PEGylated liposomes remained in circulation for long periods of time, whereas a novel type of liposomes (which we named AmbiMACs) selectively targeted macrophages. Upon laser wounding of the tail, both types of liposomes were shown to accumulate near the wounding site. Encapsulation of PLP in the PEGylated liposomes and AmbiMACs increased its potency to inhibit the inflammatory response. However, encapsulation of PLP in either type of liposome reduced its inhibitory effect on tissue regeneration, and encapsulation in PEGylated liposomes attenuated the activation of glucocorticoid-responsive gene expression throughout the body. Thus, by exploiting the unique possibilities of the zebrafish animal model to study the biodistribution as well as the anti-inflammatory and adverse effects of liposomal formulations of PLP, we showed that PEGylated liposomes and AmbiMACs increase the therapeutic ratio of this GC drug.