Optimizing Surface\nMaleimide/cRGD Ratios Enhances\nTargeting Efficiency of cRGD-Functionalized Nanomedicines

Thiol–maleimide (MI) chemistry is a cornerstone\nof bioconjugation\nstrategies, particularly in the development of drug delivery systems.\nThe cyclic arginine–glycine–aspartic acid (cRGD) peptide,\nrecognized for its ability to target the integrin α<sub>v</sub>β<sub>3</sub>, is commonly employed to functionalize maleimide-bearing\nnanoparticles (NPs) for fabricating cRGD-functionalized nanomedicines.\nHowever, the impact of cRGD density on tumor targeting efficiency\nremains poorly understood. In this study, we investigate how varying\nMI/cRGD ratios affect the biological fate of cRGD-functionalized nanomedicines.\nUsing a model system of nanomedicines self-assembled from phthalocyanine\nderivatives and PEG–PLA block copolymers, we demonstrate that\nan optimized cRGD/MI ratio can markedly alter the protein corona composition,\nleading to increased albumin adsorption, while MI-free cRGD-functionalized\nnanomedicines attract immunoglobulins and complement proteins. Our\nfindings reveal that higher cRGD densities, contrary to expectations,\ndo not enhance tumor targeting but instead promote sequestration in\nthe liver and spleen. However, the presence of MI moieties can significantly\nmitigate this sequestration of cRGD-functionalized nanomedicines by\npromoting the formation of an albumin-rich protein corona on nanomedicines.\nThese insights highlight the capacity of MI moieties in improving\nthe targeting and therapeutic effects of cRGD-functionalized nanomedicines,\nproviding refined strategies to maximize the efficacy of nanomedicines\nwhile minimizing off-target effects.