Optimizing Surface Maleimide/cRGD Ratios Enhances Targeting Efficiency of cRGD-Functionalized Nanomedicines

, is commonly employed to functionalize maleimide-bearing nanoparticles (NPs) for fabricating cRGD-functionalized nanomedicines. However, the impact of cRGD density on tumor targeting efficiency remains poorly understood. In this study, we investigate how varying MI/cRGD ratios affect the biological fate of cRGD-functionalized nanomedicines. Using a model system of nanomedicines self-assembled from phthalocyanine derivatives and PEG-PLA block copolymers, we demonstrate that an optimized cRGD/MI ratio can markedly alter the protein corona composition, leading to increased albumin adsorption, while MI-free cRGD-functionalized nanomedicines attract immunoglobulins and complement proteins. Our findings reveal that higher cRGD densities, contrary to expectations, do not enhance tumor targeting but instead promote sequestration in the liver and spleen. However, the presence of MI moieties can significantly mitigate this sequestration of cRGD-functionalized nanomedicines by promoting the formation of an albumin-rich protein corona on nanomedicines. These insights highlight the capacity of MI moieties in improving the targeting and therapeutic effects of cRGD-functionalized nanomedicines, providing refined strategies to maximize the efficacy of nanomedicines while minimizing off-target effects.