Beyond gadolinium: The potential of manganese nanosystems in MRI and multimodal imaging agents

Manganese-based nanoparticles (Mn-NPs) hold great promise as MRI contrast agents and components of theranostic nanoplatforms, serving as a promising alternative to the more established gadolinium(III)-based nanosystems. This potential stems from their unique physicochemical properties and improved safety profile. This review introduces the fundamental principles of relaxation to highlight the key physicochemical characteristics of Mn-based nanosystems that influence their effectiveness. We primarily examine two oxidation states of manganese, Mn(II) and Mn(III), to demonstrate the efficacy of Mn-NPs as relaxation probes, with a brief discussion of one Mn(IV) system. Subsequently, we review recent studies on Mn-NP-based MRI contrast agents, focusing on the correlation between nanoparticle structure and the oxidation state of the paramagnetic centre. For Mn(II), the most common strategy involves utilizing stable Mn-chelates anchored to or encapsulated within the nanoparticles. In contrast, for the higher oxidation state, Mn(III), Mn(III)-porphyrin and phthalocyanine NPs are the primary non-Mn oxide nanosystems of choice. Regarding nanoplatform composition, Mn(II)-based platforms utilizing lipids (micelles or liposomes), polysaccharides (nanogels), dendrimers, metal-organic frameworks, inorganic NPs, and silicas are among the most frequently investigated. While numerous in vitro and in vivo animal MRI studies of Mn nanoplatforms have been reported, none have yet received clinical approval. We describe innovative surface modification and functionalization procedures designed to improve NP characteristics (e.g. , size, stability, dispersibility, relaxivity, targeting, and toxicity) and impart multifunctionality for multimodal imaging. These strategies may provide valuable guidance for the development of Mn-NPs toward future clinical applications, particularly in cancer theranostics. Statement of significance This review provides a critical analysis of the current landscape of Mn-based nanoparticles, which are increasingly being explored as MRI contrast agents and for multimodal imaging. This growing interest is largely driven by concerns over the potential toxicity and environmental impact of traditional Gd-based systems. The review introduces the key structural and dynamic parameters that determine the effectiveness of these nanosystems, highlighting their direct relationship with molecular design. It also examines the crucial stability and kinetic inertness requirements that influence their development. By critically discussing selected recent examples across a diverse range of nanosystems, including micelles, liposomes, silica-based platforms, and MOFs, this review identifies existing challenges and provides key insights to guide their future clinical translation.