Moon, Hye-ran Cho, Bo Kyung Kang, Seung Hyun Ryu, Ju Hee Kwon, Ick Chan 2025-07-18T02:30:06Z 2025-07-18T02:30:06Z 2025-07-18 2025-09 0168-3659 https://pubs.kist.re.kr/handle/201004/152752 Macropinocytosis, a cellular process often hyperactivated in cancers with KRAS mutations or PTEN deficiencies, plays a crucial role in tumor survival and therapy. While inhibiting this pathway has been explored as a strategy to deprive cancer cells of essential nutrients, recent advances in nanotechnology offer an innovative approach that exploits macropinocytosis for selective drug delivery. Engineered therapeutics, including nanoparticles, peptide-drug conjugates, and macromolecule-bound drugs, leverage the elevated macropinocytic activity in tumor cells to enhance drug uptake, thereby improving treatment efficacy while minimizing off-target effects. This review provides a comprehensive examination of the molecular mechanisms regulating macropinocytosis in cancer, addressing both intrinsic factors, such as oncogenic mutations, and extrinsic influences from the tumor microenvironment. We explore both inhibition strategies and therapeutic exploitation of macropinocytosis in cancer therapy, focusing specifically on the latest innovations in engineered therapeutics designed to enhance selective drug delivery. By addressing the challenges of translating macropinocytosis-targeting therapies into clinical practice, including tumor heterogeneity and drug resistance, this review highlights how modulating macropinocytosis presents new opportunities for more effective and personalized cancer treatments. English Elsevier BV Targeting and exploiting macropinocytosis in cancer therapy Article 10.1016/j.jconrel.2025.113962 1 Journal of Controlled Release, v.385 Journal of Controlled Release 385 N scie scopus 001517372500003 Chemistry, Multidisciplinary Pharmacology & Pharmacy Chemistry Pharmacology & Pharmacy Article ACTIVATION KRAS CONJUGATE PROTEINS MACROPHAGES METABOLISM RESISTANT PEPTIDES STRATEGY DELIVERY Macropinocytosis RAS mutation Selective drug delivery Albumin binding Dextran