Enhanced skin delivery of biomacromolecules using hollow sponge spicules

Abstract This study introduces hollow sponge Haliclona sp. spicules (oSHS) as an innovative microneedle technology for enhancing the skin delivery of biomacromolecules. oSHS were developed by etching SHS in 2 mol/L NaOH for 48 h, optimizing hollow channel formation while preserving structural integrity. In vitro experiments demonstrated that oSHS significantly enhanced drug absorption efficiency compared to SHS, microneedles, roller microneedles, and iontophoresis alone. Combining oSHS with iontophoresis yielded a synergistic effect, increasing biomacromolecule delivery by up to 35.09% ( p <0.05). In vivo skin delivery of ovalbumin (OVA) via oSHS elicited immune responses comparable to subcutaneous injection, with elevated OVA‐specific IgE and IL‐4 levels. A mathematical model was developed to describe oSHS‐mediated permeation, revealing dose‐dependent delivery and uniform distribution of biomacromolecules in deep skin layers, contrasting with localized accumulation from injections. Safety assessments confirmed minimal and reversible skin irritation, resolving within 72 h. These findings highlight oSHS as a safe, efficient, and scalable strategy for skin delivery of proteins, nucleic acids, and other macromolecules, offering significant potential for non‐invasive therapeutic applications.