Internal Stimuli-Responsive Nanocarriers for Dermal and Transdermal Drug Delivery: Mechanisms, Materials, and Translational Challenges.

INTRODUCTION: There are several problems with cutaneous or transdermal drug delivery, including suboptimal drug penetration, an insufficient amount of time for the drug to remain at the target, and drug instability. In response to intrinsic biological stimuli in diseased epidermal tissues, stimuli-responsive nanocarriers also called intelligent or smart delivery systems emerged to overcome these limitations and deliver various therapeutic agents. METHODS: In this study, the literature on internal stimuli-responsive nanocarriers for dermal and transdermal delivery reported in review articles/research articles from 2015 to 2026 was reviewed using Google Scholar, ScienceDirect, and PubMed as the primary databases. Relevant patents were identified by using Espacenet and Google Patents. There was no systematic quantitative synthesis, but important data were presented following qualitative synthesis. RESULTS: Enzyme-responsive systems for hyaluronidase, matrix metalloproteinases, and lipases were developed for targeted drug delivery to infection and inflammation sites. pH-sensitive nanocarriers used the acidic change in diseased skin for enhanced penetration and improved therapeutic efficiency. Glucose-responsive systems are promising to facilitate the targeted delivery of drugs to promote healing of diabetic wounds in hyperglycemia. Furthermore, drug delivery was controlled by redox-sensitive transporters, which benefited from the high levels of glutathione and reactive oxygen species in inflammatory skin. DISCUSSION: Longer cutaneous residency, less systemic exposure, and lower therapeutic dosages may explain why these smart systems may outperform conventional formulations. A relatively new development in dermatological care is the integration of multiple response systems into one platform. CONCLUSION: Internal stimuli-responsive nanocarriers are an alternative strategy for the treatment of skin diseases by combining the delivery of drug molecules with disease-specific biological signals. This new strategy may enable safer and more efficient dermal and transdermal delivery of a wide range of medicinal compounds.