The complexity of hard-to-treat diseases strongly undermines the therapeutic potential of available treatment options. Therefore, a paradigm shift from monotherapy toward combination therapy has been observed in clinical research to improve the efficiency of available treatment options. The advantages of combination therapy include the possibility of synchronous alteration of different biological pathways, reducing the required effective therapeutic dose, reducing drug resistance, and lowering the overall costs of treatment. The tunable physical properties, excellent biocompatibility, facile preparation, and ease of administration with minimal invasiveness of injectable hydrogels (IHs) have made them excellent candidates to solve the clinical and pharmacological limitations of present systems for multitherapy by direct delivery of therapeutic payloads and improving therapeutic responses through the formation of depots containing drugs, genes, cells, or a combination of them in the body after a single injection. In this review, currently available methods for the design and fabrication of IHs are systematically discussed in the first section. Next, as a step toward establishing IHs for future multimodal synergistic therapies, recent advances in cancer combination therapy, wound healing, and tissue engineering are addressed in detail in the following sections. Finally, opportunities and challenges associated with IHs for multitherapy are listed and further discussed.
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