Safe implementation of nanotechnology and nanomedicine requires an in-depth understanding of the life cycle of nanoparticles in the body. Here, we investigate the long-term fate of gold/iron oxide heterostructures after intravenous injection in mice. We show these heterostructures degrade in vivo and that the magnetic and optical properties change during the degradation process. These particles eventually eliminate from the body. The comparison of two different coating shells for heterostructures, amphiphilic polymer or polyethylene glycol, reveals the long lasting impact of initial surface properties on the nanocrystal degradability and on the kinetics of elimination of magnetic iron and gold from liver and spleen. Modulation of nanoparticles reactivity to the biological environment by the choice of materials and surface functionalization may provide new directions in the design of multifunctional nanomedicines with predictable fate.

Several studies propose nanoparticles for tumor treatment, yet little is known about the fate of nanoparticles and intimate interactions with the heterogeneous and ever-evolving tumor environment. The latter, rich in extracellular matrix, is responsible for poor penetration of therapeutics and represents a paramount issue in cancer therapy. Hence new strategies start aiming to modulate the neoplastic stroma. From this perspective, we assessed the efficacy of 19 nm PEG-coated iron oxide nanocubes with optimized magnetic properties to mediate mild tumor magnetic hyperthermia treatment. After injection of a low dose of nanocubes (700 μg of iron) into epidermoid carcinoma xenografts in mice, we monitored the effect of heating nanocubes on tumor environment. In comparison with the long-term fate after intravenous administration, we investigated spatiotemporal patterns of nanocube distribution, evaluated the evolution of cubes magnetic properties, and examined nanoparticle clearance and degradation processes. While inside tumors nanocubes retained their magnetic properties and heating capacity throughout the treatment due to a mainly interstitial extracellular location, the particles became inefficient heaters after cell internalization and transfer to spleen and liver. Our multiscale analysis reveals that collagen-rich tumor extracellular matrix confines the majority of nanocubes. However, nanocube-mediated hyperthermia has the potential to "destructure" this matrix and improve nanoparticle and drug penetration into neoplastic tissue. This study provides insight into dynamic interactions between nanoparticles and tumor components under physical stimulation and suggests that nanoparticle-mediated hyperthermia could be used to locally modify tumor stroma and thus improve drug penetration.