Transdermal Drug Delivery Using Lipid-Based Nanocarriers: A Systematic Comparative Overview

Abstract

Lipid-based nanocarriers have emerged as highly promising systems in the development of advanced pharmaceutical formulations aimed at improving therapeutic efficacy, drug penetration, and safety profiles. Their intrinsic biocompatibility, biodegradability, and structural resemblance to biological membranes allow these carriers to encapsulate both hydrophilic and lipophilic drugs efficiently while minimizing systemic toxicity. Transdermal drug delivery, an important route for managing local and systemic conditions affecting the skin, eyes, rectum, and vagina, benefits greatly from these nanoscale systems due to their ability to overcome the barrier properties of the stratum corneum. The inherent flexibility, small size, and lipid composition of nanocarriers such as liposomes, transferosomes, invasomes, and ethosomes facilitate deeper skin penetration and controlled or sustained release of therapeutic agents. As a result, lipid-based nanocarriers enhance drug stability, prolong residence time, and improve patient compliance when compared to conventional dosage forms. Their application extends across various therapeutic areas, including dermatological disorders, inflammatory conditions, localized infections, and targeted chemotherapy. This review provides a comprehensive overview of the types of lipid-based nanocarriers employed in transdermal drug delivery, highlighting their structural characteristics, mechanisms of skin permeation, advantages, and inherent limitations. Furthermore, it discusses commonly used preparation techniques, including thin-film hydration, ethanol injection, ultrasonication, high-pressure homogenization, and microemulsion methods, along with key characterization parameters such as vesicle size, zeta potential, entrapment efficiency, deformability, and stability. Overall, the paper emphasizes the growing significance of lipid-based nanocarriers as versatile, effective, and innovative tools for enhancing transdermal drug delivery and expanding the future possibilities of topical and systemic therapeutic interventions.

Introduction

Lipid-based transport systems have gained significant attention in pharmaceutical research for enhancing drug safety and therapeutic effectiveness. Their biocompatibility, biodegradability, and structural similarity to the skin’s natural lipids make them ideal for transdermal drug delivery. These carriers interact effectively with the epidermal lipid membrane, improving penetration through the skin—a route valued for its noninvasive nature, controlled release, and avoidance of first-pass metabolism. However, challenges remain due to the skin’s strong barrier function, variable hydration levels, and limitations in transporting large or ionizable molecules, often resulting in slow penetration and inadequate drug levels.

Traditional enhancement techniques—such as iontophoresis, electroporation, microneedles, and chemical permeation enhancers—can improve delivery but often cause irritation or other side effects. Lipid-based nanoformulations offer a safer alternative: their nanoscale size increases surface area, allowing deeper and more efficient drug transport.

Advantages

Lipid-based topical delivery systems provide several key benefits:

• Enhanced skin permeation: Their lipid similarity allows temporary softening of the skin barrier, improves contact area, and enables targeted follicular delivery.

• High biocompatibility: Physiological lipids reduce irritation and toxicity.

• Protection and stability of drugs: Encapsulation prevents degradation from environmental factors and prolongs shelf life.

• Controlled and sustained release: Lipid carriers can form reservoirs in the skin, providing long-lasting therapeutic effects with less frequent dosing.

Disadvantages

Despite their promise, these systems face challenges such as:

• Stability issues during storage (aggregation or leakage).

• High production cost and difficulty scaling up.

• Lack of uniform particle size and structural consistency.

• Limited drug-loading capacity.

• Short circulation time and potential immune reactions.

• Requirement for specialized expertise during formulation.

Types and Composition

Common lipid-based nanocarriers include liposomes, transferosomes, ethosomes, transethosomes, archaeosomes, phytosomes, solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs), invasomes, and pharmacosomes. Their compositions involve phospholipids, cholesterol, surfactants, ethanol, terpenes, solid and liquid lipids, and phytoconstituents depending on the type.

Preparation Methods

Manufacturing approaches—such as thin-film hydration, high-pressure homogenization, ultrasonication, microemulsion techniques, and solvent evaporation—directly influence particle size, drug entrapment, stability, and release patterns. These methods allow the creation of stable nanosystems capable of improved dermal penetration and prolonged therapeutic effect.

Conclusion

Lipid nanoparticles represent a promising and versatile platform for transdermal drug delivery, offering distinct advantages over conventional topical formulations. Their small size, biocompatibility, and ability to encapsulate both hydrophilic and lipophilic compounds enable enhanced drug stability, controlled release, and improved penetration through the stratum corneum. Solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs), and related lipid-based systems have demonstrated the capacity to overcome major barriers of the skin by modifying surface properties, optimizing lipid composition, and leveraging occlusive effects that enhance hydration and permeation. Despite these advances, several challenges remain, including long-term stability, large-scale production, variability in skin permeation, and the need for standardized evaluation methods. Continued research integrating advanced characterization techniques, innovative lipid materials, and in-vivo validation will be critical to translate these systems from laboratory research to clinical applications. Overall, lipid nanoparticles hold significant potential to transform transdermal therapy by enabling non-invasive, patient-friendly, and efficient drug administration.

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Copyright

Copyright © 2025 Durga Pallavi Arumilli, Jhansi Satya Sri Lakshmi Vobilisetti, Siva Ramyatha Tetali, Vishnu Sai Veeranki, Narayana Raju P, Bhaskara Raju V. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.