This research paper introduces a novel transdermal delivery platform based on fluorocarbon-modified chitosan (FCS) for efficient non-invasive delivery of biomacromolecules. The FCS nanocomplexes effectively penetrate the skin via intercellular and transappendageal routes. In melanoma-bearing mice, transdermal delivery of immune checkpoint blockade antibodies induced stronger immune responses and reduced systemic toxicity compared to intravenous injection. Transdermal delivery of a SARS-CoV-2 vaccine also resulted in comparable humoral immunity and improved cellular immunity and immune memory. The platform demonstrated efficacy in rabbit and porcine skin models, suggesting broad applicability for delivering biotherapeutics.