Leveraging endogenous proteins to improve cancer nanomedicine delivery

Nanoparticle performance in vivo is strongly shaped by interactions with the complex biological environment. Upon exposure to biological fluids, endogenous proteins rapidly adsorb onto nanoparticle surfaces to form a protein corona, which redefines the nanoparticle's biological identity and influences its biodistribution, cellular interactions, and tumor accumulation. Rather than viewing protein adsorption solely as a barrier, growing evidence suggests that endogenous proteins can be strategically leveraged to enhance nanoparticle tumor delivery. This review provides a comprehensive overview of recent advances in endogenous protein-mediated nanoparticle delivery in cancer. We first discuss six major protein families implicated in both cancer biology and nanoparticle delivery, including apolipoproteins, albumin, vitronectin, transferrin, complement proteins, and coagulation factors. Together, these proteins illustrate how cancer-associated receptor overexpression and dysregulated protein metabolism can be exploited to enhance cancer-selective nanoparticle delivery. We then examine how cancer reshapes protein profiles in tumor interstitial fluid and in the blood plasma of cancer patients and discuss the implications of these altered proteomes for nanoparticle corona formation and targeting. Engineering strategies to modulate endogenous protein-nanoparticle interactions are also reviewed, including tuning nanoparticle surface properties, protein pre-incubation, covalent conjugation, crosslinking, and computationally guided approaches. Finally, we address current challenges, including interpatient variability, corona reproducibility, and translational considerations. By integrating tumor biology with materials engineering, this review demonstrates that endogenous protein-mediated targeting provides a mechanistically informed framework for advancing precision cancer nanomedicine.