Transcytosis‐Inducing Multifunctional Albumin Nanomedicines with Deep Penetration Ability for Image‐Guided Solid Tumor Treatment

Abstract Transcytosis is an active transcellular transportation pathway that has garnered interest for overcoming the limited deep penetration of nanomedicines in solid tumors. In this study, a charge‐convertible nanomedicine that facilitates deep penetration into solid tumors via transcytosis is designed. It is an albumin‐based calcium phosphate nanomedicine loaded with IR820 (mAlb‐820@CaP) for high‐resolution photoacoustic imaging and enhanced photothermal therapy. Biomineralization on the surface stabilizes the albumin‐IR820 complex during circulation and provides calcium ions (Ca 2+ ) for tissue penetration on degradation in an acidic environment. pH‐triggered transcytosis of the nanomedicine enabled by caveolae‐mediated endocytosis and calcium ion‐induced exocytosis in 2D cellular, 3D spheroid, and in vivo tumor models is demonstrated. Notably, the extravasation and penetration ability of the nanomedicine is observed in vivo using a high‐resolution photoacoustic system, and nanomedicine shows the most potent photothermal antitumor effect in vivo. Overall, the strategy provides a versatile theragnosis platform for both noninvasive photoacoustic imaging and high therapeutic efficiency resulting from deep penetration of nanomedicine.