<p>Nanotechnology has propelled the development of nanodrug delivery systems (NDDS) with remarkable potential in disease diagnosis and therapy. Nevertheless, conventional NDDS relying on exogenous nano-carriers suffer from intrinsic limitations, including suboptimal drug-loading capacity and biocompatibility issues. In this context, carrier-free nanodrug delivery systems (CFNDDS), constructed through the intrinsic self-assembly of therapeutic molecules, have emerged as a paradigm-shifting alternative. CFNDDS enables drug loading efficiency close to the theoretical maximum, while effectively avoiding carrier-associated toxicity, thereby maximizing drug efficacy. This review meticulously elucidates the fundamental driving forces that regulate CFNDDS self-assembly and summarizes innovative delivery strategies based on single-drug, dual-drug, multi-drug, and prodrug modalities. Furthermore, we provide a comprehensive survey of recent advancements in CFNDDS applications for treating various diseases, including cancer, fatty liver disease, osteoarthritis, atherosclerosis, fibrosis, and antibacterial infections. Analyzing the mechanism of action and application value of CFNDDS from multiple dimensions, perspectives, and levels provides a crucial theoretical basis for developing and researching the clinical use of drugs.</p>