As cancer nanotherapeutics, the ideal multifunctional nanoparticles not only have the processing ability to accumulate effectively in tumors, but also can be excreted rapidly from the body via renal clearance after effective treatment. Melanin is an endogenous biological material, and gelatin has natural biocompatibility and biodegradability. Such materials are more promising in the development of diagnostic and therapeutic nanoplatform for future clinical translation. In this study, we have developed a kind of size-shrinkable PA/MRI theranostic agent based on gelatin fabricated ultrasmall melanin nanoparticles (MNPs-GNP). The MNPs-GNP nanoparticles, with a size of about 100 nm, presented good dispersibility, broadband light absorbance, negligible cellular cytotoxicity, preferable tumor accumulation by EPR-based passive targeting. The dual-modal imaging results showed that the nanoparticles have excellent photoacoustic (PA) imaging and nuclear magnetic resonance (MRI) imaging after tumor-bearing mice were intravenously injected with MNPs-GNP. Additionally, gelatin is the substrate of matrix metalloproteinase-2 (MMP-2), following with the degradation of gelatin nanoparticles by MMP-2, the large-size MNPs-GNP turns to be small-size melanin, which could mainly be excreted via renal clearance avoiding potential toxicity to body tissues. These preliminary results indicated that MNPs-GNP can overcome the dilemma between EPR and renal clearance, which has clinical application potentiality as a PA/MRI dual-modal candidate agent for cancer theranostics.

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