Novel Dual Strategy Based on EPR/AT for Optimizing Therapeutic Effect by Improving Drug Delivery System Physicochemical Properties and Regulating TME

Long Chen,1,2,* Xiang Deng,1– 3,* Qian Shen,1– 3 Min Chen,4 Churong Li,2,5 Shunxi Wang1,2,6,7 1The Second Affiliated Hospital of Chengdu Medical College, Nuclear Industry 416 Hospital Chengdu, Sichuan, 610000, People’s Republic of China; 2Non-Coding RNA and Drug Discovery Key Laboratory of Sichuan Province, School of Basic Medical Sciences, Chengdu Medical College, Chengdu, Sichuan, 610550, People’s Republic of China; 3Clinical Medical College, Chengdu Medical College, Chengdu, Sichuan, 610500, People’s Republic of China; 4Department of Dermatology, Nanbu People’s Hospital, Nanchong, Sichuan, 637300, People’s Republic of China; 5Radiotherapy Center, Radiation Oncology Key Laboratory of Sichuan Province, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, University of Electronic Science and Technology of China, Chengdu, 610041, People’s Republic of China; 6Institute of Pathology & Southwest Cancer Center, the First Afliated Hospital (Southwest Hospital) of Army Medical University (Third Military Medical University), Chongqing, 400038, People’s Republic of China; 7Chongqing Institute of Advanced Pathology, Jinfeng Laboratory, Chongqing, 400039, People’s Republic of China*These authors contributed equally to this workCorrespondence: Churong Li, Email mylcr2009@163.com Shunxi Wang, Email sx_wang1024@126.comAbstract: The clinical advancement of cancer nanomedicine is significantly hindered by its limited accumulation in tumors, a key factor behind the frequent failure of nanodrugs in clinical trials. The effectiveness of these nanodrugs is closely tied to their route of administration, whether oral, transdermal, intravenous, or intracerebral, as each path presents unique physiological barriers that impede bioavailability and precise tumor targeting. Among the major causes of poor accumulation are rapid clearance by the mononuclear phagocyte system, opsonization accompanied by protein corona formation, renal filtration, and the abnormal, heterogeneous nature of tumor vasculature that restricts passive targeting via the enhanced permeability and retention (EPR) effect. In response, active targeting (AT) strategies have been widely explored, including surface modification with ligands, antibodies, or aptamers designed to bind specifically to overexpressed receptors on cancer cells or blood vessels. Despite these efforts, challenges such as the dense extracellular matrix, elevated interstitial fluid pressure, and the notable inconsistency of the EPR effect between animal models and human patients continue to limit therapeutic penetration. This review offers a systematic examination of nanodrug delivery pathways and the reasons behind their inadequate accumulation, highlighting the potential of both active targeting and combined passive-active strategies to enhance tumor-specific delivery. Overcoming these biological barriers through refined nano-design is crucial for developing the next generation of nanomedicines with improved tumor accumulation and treatment outcomes.Keywords: nanomedicine, EPR effect, active targeting, tumor accumulation