Chronic non-healing wounds persist as a substantial burden for healthcare systems, influenced by factors such as aging, diabetes, and obesity. In contrast to the traditionally pro-regenerative emphasis of therapies, the recognition of the immune system integral role in wound healing has significantly grown, instigating an approach shift towards immunological processes. Thus, this review explores the wound healing process, highlighting the engagement of the immune system, and delving into the behaviors of innate and adaptive immune cells in chronic wound scenarios. Moreover, the article investigates biomaterial-based strategies for the modulation of the immune system, elucidating how the adjustment of their physicochemical properties or their synergistic combination with other agents such as drugs, proteins or mesenchymal stromal cells can effectively modulate the behaviors of different immune cells. Finally this review explores various strategies based on synthetic and biological nanostructures, including extracellular vesicles, to finely tune the immune system as natural immunomodulators or therapeutic nanocarriers with promising biophysical properties.