Mechanisms and therapeutic design of stimuli-responsive vesicular nanocarriers for melanoma

Cutaneous melanoma is an extremely aggressive form of cancer and a major cause of death worldwide. Localized delivery by transdermal application is an alternative to systemic chemotherapy, which has a low therapeutic index and off-target toxicity. The clinical translation of topical oncology is hindered by a formidable dual barrier: the highly ordered and rigid lipid-protein barrier of the stratum corneum (SC) and the fibrotic, restrictive tumor microenvironment (TME) of the melanoma. In this review, the paradigm shift from passive delivery vehicles to stimuli-responsive vesicular nanocarriers, which are systematically designed to overcome these physical and biochemical barriers, is critically explored. We critically analyse the bioengineering of stimuli-responsive lipidic systems, such as nanovesicular systems, that preserve the deformability of the SC whilst leveraging specific pathophysiological features of the melanoma TME. Moreover, in order to close the loop between elegant concepts and clinical feasibility, we specifically discuss the major translational hurdles that currently hinder this field, such as manufacturing scalability issues, regulatory hurdles, and the lack of adequate standard murine models. Key structural modifications are discussed, including the use of extracellular acidosis via charge reversal and acid-cleavable linkages, oxidative stress via ROS-responsive thioether and thioketal phase transitions, and enzyme overexpression via matrix metalloproteinase (MMP)-triggered de-PEGylation. These intelligent nanocarriers offer a very promising approach to achieving maximum intracellular accumulation by enabling on-demand payload release at a spatiotemporally controlled location within the malignant stroma. Such responsive systems are shown to routinely produce significant enhancements in deep transdermal permeation and even greater enhancements in local cytotoxicity than passive liposomes. Finally, how this strategy is able to overcome the restrictions of the heterogeneous enhanced permeability and retention (EPR) effect and substantially enhance the therapeutic index of targeted melanoma therapy.