<p>The delivery of macromolecules through dermal and transdermal routes presents both significant challenges and transformative opportunities in therapeutic applications. This review highlights the most recent advancements and innovative strategies aimed at overcoming the barriers associated with macromolecular delivery. Cutting-edge approaches such as the use of adjuvants (e.g., hyaluronic acid-based and chemical penetration enhancers), bioactive peptides with diverse functionalities, and mechanical force techniques—including iontophoresis, microneedles, and electroporation—are thoroughly explored. While various strategies have been implemented to enhance skin delivery, they often present significant challenges, particularly for macromolecules. Addressing these challenges requires integrating novel technologies and understanding the interplay between biological barriers and delivery mechanisms. Furthermore, the role of nanotechnology, through systems like nanoemulsions, polymeric nanoparticles, and transferosomes, is examined for its ability to protect macromolecules and regulate their release. Notably, this review provides unique perspectives on the interplay between these strategies and their potential to revolutionise future therapeutics. By highlighting key trends and advancements in macromolecule delivery, this review underscores the importance of innovative approaches in overcoming existing barriers and enabling efficient drug administration.</p> Graphical Abstract <p></p>