Hydrophobic sponge spicule-mediated transdermal vaccination combines controlled skin inflammation as self-adjuvant with dual immune activation

We developed hydrophobic sponge (Haliclona sp.) spicules (hSHS) through surface modification of natural spicules (SHS) with monolayers of hydrophobic functional groups (e.g., alkyl and phenyl moieties). Utilizing ovalbumin (OVA) as a model protein antigen, we fabricated a transdermal vaccine (OVA@hSHS) through hydrophobic adsorption of OVA onto hSHS. Upon topical application, OVA@hSHS effectively penetrated the skin via microneedle-like mechanical puncture, enabling direct intradermal antigen access. Subsequent exposure to the physiological milieu triggered sustained antigen release with progressive diffusion into deeper skin layers. The system exhibited immunoadjuvant activity mediated by physical microinjury (i.e., skin cell disruption), which stimulated pro-inflammatory cytokine secretion and induced macrophage polarization toward the M1 phenotype. Within this inflammatory microenvironment, recruited antigen-presenting cells efficiently internalized and processed antigens, leading to enhanced maturation and antigen presentation. This ultimately elicited a robust and balanced immune response—combining potent humoral and cellular immunity with potential durable memory effects. Notably, the OVA@hSHS-induced skin inflammation was self-limiting, with skin tissue capable of autonomously restoring inflammatory homeostasis. In summary, hSHS offers a simple yet versatile platform for developing transdermal protein-based vaccines.