Advancing immunotherapy using biomaterials to control tissue, cellular, and molecular level immune signaling in skin

Immunotherapies have been transformative in many areas, including cancer treatments, allergies, and autoimmune diseases. However, significant challenges persist in extending the reach of these technologies to new indications and patients. Some of the major hurdles include narrow applicability to patient groups, transient efficacy, high cost burdens, poor immunogenicity, and side effects or off-target toxicity that results from lack of disease-specificity and inefficient delivery. Thus, there is a significant need for strategies that control immune responses generated by immunotherapies while targeting infection, cancer, allergy, and autoimmunity. Being the outermost barrier of the body and the first line of host defense, the skin presents a unique immunological interface to achieve these goals. The skin contains a high concentration of specialized immune cells, such as antigen-presenting cells and tissue-resident memory T cells. These cells feature diverse and potent combinations of immune receptors, providing access to cellular and molecular level control to modulate immune responses. Thus, skin provides accessible tissue, cellular, and molecular level controls that can be harnessed to improve immunotherapies. Biomaterial platforms - microneedles, nano- and micro-particles, scaffolds, and other technologies - are uniquely capable of modulating the specialized immunological niche in skin by targeting these distinct biological levels of control. This review highlights recent pre-clinical and clinical advances in biomaterial-based approaches to target and modulate immune signaling in the skin at the tissue, cellular, and molecular levels for immunotherapeutic applications. We begin by discussing skin cytoarchitecture and resident immune cells to establish the biological rationale for skin-targeting immunotherapies. This is followed by a critical presentation of biomaterial-based pre-clinical and clinical studies aimed at controlling the immune response in the skin for immunotherapy and therapeutic vaccine applications in cancer, allergy, and autoimmunity.