Transdermal delivery of biologics.

Biologics, including peptides, proteins, antibodies, vaccines and nucleic acid-based therapeutics, have transformed the management of chronic, metabolic, inflammatory, oncological and infectious diseases. Despite their clinical success, their wider use remains constrained by invasive administration routes, poor patient acceptability and formulation challenges related to instability, degradation, aggregation and immunogenicity. Transdermal delivery offers a minimally invasive alternative with potential for controlled, sustained and patient-friendly administration; however, the stratum corneum and viable skin layers strongly restrict the transport of large, hydrophilic and structurally sensitive biomolecules. This review critically evaluates conventional and emerging strategies for transdermal delivery of biologics through a biologic-specific and translational framework. Chemical permeation enhancers, ionic liquids, iontophoresis, sonophoresis, electroporation, microdermabrasion, microneedles, laser and radiofrequency ablation, cell-penetrating peptides, nanocarriers, jet injection, wearable systems and hybrid platforms are compared according to their mechanisms, biologic compatibility, dose capacity, delivery depth, scalability and clinical readiness. Particular attention is given to the relationship between biologic class, dose requirement, local versus systemic exposure, lymphatic uptake, microchannel closure, formulation stability and pharmacokinetic feasibility. Recent advances in smart and stimuli-responsive systems, 3D printing, bioelectronic interfaces and artificial intelligence/machine learning (AI/ML)-guided formulation design are also discussed. Key translational barriers are considered, including biologic stability, dose scalability, skin metabolism, immune responses, manufacturing reproducibility, sterility assurance, usability and regulatory complexity. Integrating mechanistic, formulation, device and translational perspectives, this review identifies realistic opportunities for transdermal biologics delivery while critically outlining the remaining limitations for clinical implementation.