Objective <p>This review focuses on critically analyzing recent breakthroughs in smart hybrid microneedle transferosome systems of co-delivery of peptide biologics and gene modulators pertaining to design principles, synergistic mechanisms, and translational opportunities for upholding next-generation targeted transdermal therapeutics.</p> Methods <p>The latest literature was systematically examined on DMN-integrated transferosomal systems, smart polymer characteristics, and lipid vesicle engineering on controlled drug delivery. Selected studies also looked into skin permeability, targeted delivery, therapeutic performance, preclinical and early clinical studies, and AI-equipped formulation design.</p> Results <p>Transferosomes manifest ultra-deformability and improved skin penetration, which is a plus when used with DMNs in what is an altogether less intrusive and user-friendly mode of administration, enhancing gene and peptide stability, affordability, and acceptance. Several reported applications for therapeutic effects against metabolic disorders, cancer immunotherapy, and neurological applications have been published. The combination of smart polymers with AI- generated approaches reinforces formulation performance and robustness. Still, the majority of studies remain limited to only proof of concept without comparatives and/or long-term data, raising concerns for effectiveness and safety reproducibility across different microneedle-transferosome platforms.</p> Conclusion <p>DMN-transferosomes systems synergistically integrate the efficacy of nanocarrier stability with minimally invasive delivery. Further, so many gaps persist: scaled-up production, physical instability of the formulation, regulatory testing, and low level of clinical adoption. Smart microneedles, multifunctional nanocarriers, and predictive modelling innovations are all expected to rapidly hasten the translatability of next-generation gene and peptide therapies systems into the clinics.</p>