Multifunctional nanoparticle-mediated combining therapy for human diseases Combining existing drug therapies is essential in developing new therapeutic agents for disease prevention and treatment. Preclinical studies have shown that certain drug combinations are effective in treating various human diseases. Combinatorial therapy, which involves delivering two or more drugs together, is now being pursued to combat major clinical illnesses such as cancer, atherosclerosis, pulmonary hypertension, myocarditis, rheumatoid arthritis, inflammatory bowel disease, metabolic disorders, and neurodegenerative diseases. Nanoparticle (NP)-mediated drug delivery systems, including liposomal NPs, polymeric NPs, and nanocrystals, are of great interest in combinatorial therapy due to their ability to target drug delivery, extend drug release, and increase drug stability to avoid rapid clearance at infected areas. This review summarizes various disease targets, preclinical or clinically approved drug combinations, and the development of multifunctional NPs for combining therapy, emphasizing combinatorial therapeutic strategies for severe clinical diseases. It also discusses the challenges of developing NP-codelivery and translation, and provides potential approaches to address the limitations. Combining multiple drugs may result in additive, synergistic, or antagonistic effects. Synergistic effects occur when drugs work together on a complex biological network rather than a single target. Synergy can be pharmacodynamic (PD) or pharmacokinetic (PK). PD synergy involves targeting different pathways, while PK synergy affects drug absorption, bioavailability, distribution, or metabolism. NPs allow synergistic effects by improving solubility, PK consistency, and diseased-site accumulation of two drugs. The combination index (CI) is used to evaluate the combinatory effect, indicating synergistic (CI < 1), antagonistic (CI > 1), or additive (CI = 1) combinations. Cancer is a heterogeneous disorder characterized by the uncontrolled growth and proliferation of abnormal cells. Solid tumors consist of stromal cells, cancer cells, and infiltrating immune cells. The first-line treatment for most cancers is chemotherapy, but conventional chemotherapies have limitations such as drug resistance, toxicity, and poor targeting. Drug combination therapy has shown improved treatment outcomes, and nanotechnology is playing an increasing role in cancer treatment and diagnosis. Targeting specific cell-sustaining and cancer-inducing pathways is crucial for effective cancer therapy. Multifunctional NPs are emerging as a robust approach to improve combining therapy. They can load active agents into one carrier, improve drug solubility, protect the drug from decomposition, alter biodistribution, enhance tissue penetration, avoid rapid clearance, prolong half-life, and reduce off-target effects. NPs enable the simultaneous or spatial delivery of two or more drugs, allowing consistent pharmacokinetic performance and maximizing synergistic effects. NPs can be given via various routes, increasing their clinical potential. The models for evaluating combination effects include effect-based and concentration-based models. Effect-based models, such asMultifunctional nanoparticle-mediated combining therapy for human diseases Combining existing drug therapies is essential in developing new therapeutic agents for disease prevention and treatment. Preclinical studies have shown that certain drug combinations are effective in treating various human diseases. Combinatorial therapy, which involves delivering two or more drugs together, is now being pursued to combat major clinical illnesses such as cancer, atherosclerosis, pulmonary hypertension, myocarditis, rheumatoid arthritis, inflammatory bowel disease, metabolic disorders, and neurodegenerative diseases. Nanoparticle (NP)-mediated drug delivery systems, including liposomal NPs, polymeric NPs, and nanocrystals, are of great interest in combinatorial therapy due to their ability to target drug delivery, extend drug release, and increase drug stability to avoid rapid clearance at infected areas. This review summarizes various disease targets, preclinical or clinically approved drug combinations, and the development of multifunctional NPs for combining therapy, emphasizing combinatorial therapeutic strategies for severe clinical diseases. It also discusses the challenges of developing NP-codelivery and translation, and provides potential approaches to address the limitations. Combining multiple drugs may result in additive, synergistic, or antagonistic effects. Synergistic effects occur when drugs work together on a complex biological network rather than a single target. Synergy can be pharmacodynamic (PD) or pharmacokinetic (PK). PD synergy involves targeting different pathways, while PK synergy affects drug absorption, bioavailability, distribution, or metabolism. NPs allow synergistic effects by improving solubility, PK consistency, and diseased-site accumulation of two drugs. The combination index (CI) is used to evaluate the combinatory effect, indicating synergistic (CI < 1), antagonistic (CI > 1), or additive (CI = 1) combinations. Cancer is a heterogeneous disorder characterized by the uncontrolled growth and proliferation of abnormal cells. Solid tumors consist of stromal cells, cancer cells, and infiltrating immune cells. The first-line treatment for most cancers is chemotherapy, but conventional chemotherapies have limitations such as drug resistance, toxicity, and poor targeting. Drug combination therapy has shown improved treatment outcomes, and nanotechnology is playing an increasing role in cancer treatment and diagnosis. Targeting specific cell-sustaining and cancer-inducing pathways is crucial for effective cancer therapy. Multifunctional NPs are emerging as a robust approach to improve combining therapy. They can load active agents into one carrier, improve drug solubility, protect the drug from decomposition, alter biodistribution, enhance tissue penetration, avoid rapid clearance, prolong half-life, and reduce off-target effects. NPs enable the simultaneous or spatial delivery of two or more drugs, allowing consistent pharmacokinetic performance and maximizing synergistic effects. NPs can be given via various routes, increasing their clinical potential. The models for evaluating combination effects include effect-based and concentration-based models. Effect-based models, such as