Arprita Malhan, Mridul Guleria, Bijal Prajapati, Bijal Prajapati, J S Patel, Krishna Sompura, Sudarshan Singh, Subheet Kumar Jain, Bhupendra Prajapati, Bhupendra Prajapati
Ultra-deformable (UD) lipid-based nanocarriers have emerged as advanced drug delivery systems capable of overcoming critical biological barriers and improving the bioavailability of therapeutics. This review critically examines ethosomes, transethosomes, and transfersomes, with particular emphasis on their deformability-driven transport across the stratum corneum, gastrointestinal epithelium, and blood–brain barrier. The review particularly focuses on plant-derived bioactive compounds, whose therapeutic translation is often hampered by poor aqueous solubility, rapid biotransformation, and low systemic exposure. This review highlights how optimized combinations of phospholipids, edge activators, and stabilizers enhance vesicle elasticity, drug encapsulation, protection from enzymatic degradation, and controlled release. Beyond descriptive advances, this article addresses existing gaps related to stability, lipid oxidation, premature drug leakage, regulatory challenges, and the lack of scalable manufacturing strategies. Recent developments in stimuli-responsive systems, polymer–lipid conjugates, and hybrid nanocarriers are discussed as promising solutions to these limitations. By integrating mechanistic insights with formulation and translational perspectives, this review provides a consolidated framework to guide the rational design and clinical advancement of UD nanocarriers, positioning them as viable platforms for noninvasive, patient-centric, and personalized drug delivery.