Beyond one-size-fits-all: cancer biology shapes nanoparticle behavior.

Nanoparticles (NPs) are a promising tool for cancer therapy, yet few have successfully reached clinical application. Current nanomedicine development pipelines are focused on optimizing the physical properties of NPs, overlooking the impact of cancer biology on their behavior. Here, we show that the polyethyleneimine-functionalized, silica-coated gold NPs (Au@mSi-PEI) exhibit distinct accumulation and penetration patterns in 3D spheroids derived from four spheroid models (representative of lung, colon, breast, and cervical cancer). We uncover an inverse relationship between NP uptake and penetration: spheroids with slower internalization show deeper NP diffusion. Proteomic analysis revealed that tumor-specific expression of endocytic and extracellular matrix proteins underlies this variability. Our findings challenge the prevailing 'one-size-fits-all' approach and highlight the need to integrate cancer biology into NP design. Tailoring NPs to the unique cellular and extracellular features of each tumor type will be critical for developing more effective and clinically relevant nanotherapies.