Decoding the uptake pathway of nanoparticles in tumor cells: mechanisms, developments and challenges.

Nanoparticles hold transformative potential for cancer therapy through targeted drug delivery; however, inefficient uptake by tumor cells remains a major obstacle. This review elucidates the complex, multistep process by which tumor cells take up nanoparticles: how nanoparticles, starting from systemic administration, traverse the tumor vascular and stromal barriers, enter tumor cells via endocytic pathways, and ultimately exert their therapeutic effects in the cytoplasm or nucleus. It highlights the barriers nanoparticles must overcome within the tumor microenvironment to achieve truly therapeutically meaningful uptake. Additionally, this review discusses key advancements, including cell-penetrating peptides for enhanced penetration and endosomal escape, as well as the potential influence of nanoparticle physicochemical properties on uptake. Furthermore, the text explores emerging strategies, such as biomimetic cell membrane coatings, charge-reversal systems, and AI-assisted design, aimed at overcoming uptake challenges and addressing cytotoxicity issues in normal tissues. This review expands upon the established concept of delivery cascades, adopting a cellular uptake-centered perspective, it links vascular transport, matrix permeation, tumor cell internalization, intracellular transport, physicochemical design, and off-target toxicity as interdependent determinants of therapeutically meaningful delivery. It aims to provide a potential reference for the development of next-generation nanomedicines with superior tumor cell uptake capabilities and clinical translation potential.