The article reviews the advantages of nano-sized therapeutic agents over low molecular weight agents, particularly in cancer treatment. Nano-sized agents offer larger loading capacity, protection from degradation, specific targeting, and controlled release. However, their delivery into cancer tissue is primarily dependent on the enhanced permeability and retention (EPR) effect, which relies on the leaky nature of tumor vasculature and prolonged circulation. The EPR effect is influenced by factors such as regional blood flow, tumor vasculature permeability, structural barriers, and intratumoral pressure. The review discusses methods to enhance nano-agent delivery, including altering normal physiological conditions, modifying tumor vasculature or stroma, and killing cancer cells to reduce barrier function. These methods can improve drug delivery by up to 2-fold compared to non-treated tumors. The article also highlights the potential of photo-immunotherapy (PIT) to induce a super enhanced EPR effect, increasing drug delivery by up to 24-fold. Overall, the article emphasizes the importance of selective targeting of tumor vasculature without causing thrombosis for successful nano-drug delivery.The article reviews the advantages of nano-sized therapeutic agents over low molecular weight agents, particularly in cancer treatment. Nano-sized agents offer larger loading capacity, protection from degradation, specific targeting, and controlled release. However, their delivery into cancer tissue is primarily dependent on the enhanced permeability and retention (EPR) effect, which relies on the leaky nature of tumor vasculature and prolonged circulation. The EPR effect is influenced by factors such as regional blood flow, tumor vasculature permeability, structural barriers, and intratumoral pressure. The review discusses methods to enhance nano-agent delivery, including altering normal physiological conditions, modifying tumor vasculature or stroma, and killing cancer cells to reduce barrier function. These methods can improve drug delivery by up to 2-fold compared to non-treated tumors. The article also highlights the potential of photo-immunotherapy (PIT) to induce a super enhanced EPR effect, increasing drug delivery by up to 24-fold. Overall, the article emphasizes the importance of selective targeting of tumor vasculature without causing thrombosis for successful nano-drug delivery.