# Enhancement of EPR Effect for Passive Tumor Targeting: Current Status and Future Perspectives
###### Abstract
The shape and size of the nanomedicine are critical factors determining its retention in the tumor site, as they dictate its circulation time in the bloodstream, distribution across various tissues and organs, and recognition and clearance through the reticuloendothelial system (RES), which includes macrophages in the liver, spleen, and bone marrow [3; 7; 10; 13; 14]. Additionally, the lack of control over essential parameters affecting the effective delivery of nanomedicines to the target, such as their release rate, internalization, or surface modification with immune-evasive components like polyethylene glycol (PEG), and their biocompatibility has led to disappointing results in exploiting the EPR phenomenon for therapeutic purposes [3; 7; 10]. Significant heterogeneity encountered both among different tumors and within different regions of the same tumor also impacts the ineffectiveness of the EPR phenomenon at the clinical level [1; 3; 7]. For instance, tumors with increased vascular density tend to exhibit higher EPR efficacy, unlike irregularities in blood vessel structures that cause heterogeneous vascular permeability in EPR [3; 7; 8]. Furthermore, the diverse microenvironments of tumors, particularly high pericellular coverage and dense extracellular matrix (ECM), pose significant barriers for nanoparticles to approach tumors, reducing vascular permeability and effective drug distribution [3; 7]. Moreover, due to the heterogeneity in tumor perfusion, access to drugs and immune cells to the bloodstream is hindered, leading to conditions like hypoxia that promote tumor progression while conferring resistance to oxygen-dependent therapies [5]. Another factor is the increased interstitial fluid pressure (IFP) within tumor tissues, which drives nanomedicines back into circulation or even increases IFP peripherally compared to the tumor center, hindering transport from the circulatory system to the tissue [3,7]. To strengthen the EPR phenomenon and facilitate the transition of nanomedicine to clinical application, it is deemed necessary to consider the aforementioned variables by developing methods aimed at creating effective multi-stage drug delivery nano-systems for therapeutic purposes, as well as modifying the biological characteristics of solid tumors [7,15,16]. This review presents a comprehensive examination of the EPR phenomenon, focusing on recent advancements and innovative strategies aimed at enhancing its effectiveness in cancer therapy. While many reviews have addressed the fundamentals of EPR, this work highlights the unique challenges posed by tumor heterogeneity and explores cutting-edge approaches to overcoming these barriers. Specifically, we discuss the role of the TME in influencing EPR, including the impact of tumor-associated cells, ECM components, and extracellular signaling, which have been underexplored in earlier reviews. Furthermore, we emphasize novel techniques for enhancing nanocarrier permeability and retention, including physical, pharmacological, and biologically targeted strategies. In the development of drug delivery strategies and the improvement in the EPR phenomenon, inorganic, polymeric, lipid, and hybrid nanoparticles play a key role [17]. Inorganic nanoparticles (NPs), such as gold (AuNPs), silver (AgNPs), platinum (PtNPs), and zinc oxide (ZnO) nanoparticles, have proven to be particularly capable in the application of anti-cancer therapies, mainly due to their ability to affect angiogenesis and selectively target cancer cells. AuNPs, for example, have shown significant activity in inhibiting angiogenesis through interaction with VEGF-165, leading to a reduction in VEGFR-2 signaling and thus limiting cell proliferation and migration [18]. Similarly, research by [PERSON] et al. revealed that biosynthesized AuNPs enhance angiogenesis through ROS production and Akt pathway activation, promoting the formation of new blood vessels.