This review article discusses the potential of multifunctional nanoparticle (NP)-mediated combining therapy for treating various human diseases. Combinatorial therapy, which involves the use of two or more drugs, has shown promise in addressing the complex microenvironments and interconnected pathological pathways of major clinical illnesses such as cancer, cardiovascular disorders, inflammatory bowel disease, and metabolic disorders. NP-based drug delivery systems, including liposomal NPs, polymeric NPs, and nanocrystals, are highlighted for their ability to improve targeted drug delivery, extended drug release, and enhanced drug stability. The article reviews the development of multifunctional NPs for combining therapy, emphasizing their role in delivering multiple drugs simultaneously or spatially to maximize synergistic effects. It also discusses the challenges in NP-codelivery and translation, providing potential approaches to overcome these limitations. The review covers the historical development of multifunctional NPs, their applications in cancer and atherosclerosis, and the evaluation models for combination effects. Additionally, it explores the mechanisms of action and therapeutic strategies for combinatorial cancer therapy, including inhibiting proliferation, promoting apoptosis, and reversing multidrug resistance. For atherosclerosis, the article discusses the targets and strategies for combinatorial therapy, such as lipid-lowering and anti-inflammatory treatments, and the role of NP-mediated co-delivery systems like rHDL NPs in combating the disease. Overall, the review offers a comprehensive overview of the recent advancements and challenges in NP-mediated combination therapy for human diseases.This review article discusses the potential of multifunctional nanoparticle (NP)-mediated combining therapy for treating various human diseases. Combinatorial therapy, which involves the use of two or more drugs, has shown promise in addressing the complex microenvironments and interconnected pathological pathways of major clinical illnesses such as cancer, cardiovascular disorders, inflammatory bowel disease, and metabolic disorders. NP-based drug delivery systems, including liposomal NPs, polymeric NPs, and nanocrystals, are highlighted for their ability to improve targeted drug delivery, extended drug release, and enhanced drug stability. The article reviews the development of multifunctional NPs for combining therapy, emphasizing their role in delivering multiple drugs simultaneously or spatially to maximize synergistic effects. It also discusses the challenges in NP-codelivery and translation, providing potential approaches to overcome these limitations. The review covers the historical development of multifunctional NPs, their applications in cancer and atherosclerosis, and the evaluation models for combination effects. Additionally, it explores the mechanisms of action and therapeutic strategies for combinatorial cancer therapy, including inhibiting proliferation, promoting apoptosis, and reversing multidrug resistance. For atherosclerosis, the article discusses the targets and strategies for combinatorial therapy, such as lipid-lowering and anti-inflammatory treatments, and the role of NP-mediated co-delivery systems like rHDL NPs in combating the disease. Overall, the review offers a comprehensive overview of the recent advancements and challenges in NP-mediated combination therapy for human diseases.