Figure 1.

The three phases of PNP delivery and the pathophysiological barriers they encounter after systemic administration (i.e., intravenous injection). Phase I: ‘Circulation.’ After entering the bloodstream, protein corona formation on PNPs can evoke recognition by the mononuclear phagocytic system (MPS), leading to their clearance via MPS-rich organs; e.g., liver, kidney, and spleen. Therefore, to enable therapeutic concentrations of the NDDS to interact with tumors, PNPs must evade the MPS, while retaining their stability during blood circulation. Phase II: ‘Accumulation and Penetration.’ PNPs must extravasate from the bloodstream via leaky vasculature into the tumor, where they must overcome physical and physiological barriers to penetrate deep into the tumor microenvironment. Phase III: ‘Internalization and Cargo Release.’ Following endocytosis, PNPs are trafficked into endo/lysosomes and finally degraded to release their therapeutic cargo. Depending on their cargo’s mode-of-action, PNPs may need to escape (and avoid degradation) from endo/lysosomal compartments to the cytosol. TAM= tumor-associated macrophages; EPR effect = enhanced permeability and retention effect; ECM = extracellular matrix; IFP = interstitial fluid pressure.