Overcoming Biological Barriers in Cancer Therapy: Cell Membrane-Based Nanocarrier Strategies for Precision Delivery

Yuping Li,1,2 Hongfang Sun,1 Dianchao Cao,1 Yang Guo,1 Dongyang Wu,1 Menghao Yang,1 Hongming Wang,2 Xiaowei Shao,2 Youjie Li,1 Yan Liang1 1Department of Biochemistry and Molecular Biology, School of Basic Medicine, Binzhou Medical University, YanTai, ShanDong, 264003, People’s Republic of China; 2Binzhou Inspection and Testing Center, Binzhou, ShanDong, 256600, People’s Republic of ChinaCorrespondence: Yan Liang; Youjie Li, Department of Biochemistry and Molecular Biology, School of Basic Medicine, Binzhou Medical University, YanTai, ShanDong, 264003, People’s Republic of China, Tel/Fax +86 535 6913335; +86 535 6913211, Email [email protected]; [email protected]: Given the unique capabilities of natural cell membranes, such as prolonged blood circulation and homotypic targeting, extensive research has been devoted to developing cell membrane-inspired nanocarriers for cancer therapy, while most focused on overcoming one or a few biological barriers. In fact, the journey of nanosystems from systemic circulation to tumor cells involves intricate processes, encompassing blood circulation, tissue accumulation, cancer cell targeting, endocytosis, endosomal escape, intracellular trafficking to target sites, and therapeutic action, all of which pose limitations to their clinical translation. This underscores the necessity of meticulously considering these biological barriers in the design of cell membrane-mimetic nanocarriers. In this review, we delineate the functions and applications of diverse types of cell membranes in nanocarrier systems. We elaborate on the biological hurdles encountered at each stage of the biomimetic nanoparticle’s odyssey to the target, and comprehensively discuss the obstacles imposed by the tumor microenvironment for precise delivery. Subsequently, we systematically review contemporary cell membrane-based strategies aimed at overcoming these multi-level biological barriers, encompassing hybrid cell membrane (HCM) camouflage, tumor microenvironment remodeling, endosomal/lysosomal escape, multidrug resistance (MDR) reversal, optimization of nanoparticle physicochemical properties, and so on. Finally, we outline potential strategies to accelerate the development of cell membrane-inspired precision nanocarriers and discuss the challenges that must be addressed to enhance their clinical applicability. This review serves as a guide for refining the study of cell membrane-mimetic nanosystems in surmounting in vivo delivery barriers, thereby significantly contributing to advancing the development and application of cell membrane-based nanoparticles in cancer delivery. Keywords: cell membrane-mimetic, biological barriers, nanodelivery system, delivery efficiency, anti-tumor