MMP2‐Responsive Liposomes Targeting LDLR Enhance the Effectiveness of Anti‐Cancer Drugs in Treating Melanoma

ABSTRACT Current cancer therapies for solid cancers involve surgery, radiotherapy, and chemotherapy, but challenges such as tumor heterogeneity, drug resistance, and poor drug delivery hinder effective treatment. Nano‐oncology, specifically liposomes, shows promise by improving drug delivery through better pharmacokinetics and targeting, minimizing toxicity to healthy tissue. Engineered liposomes can enhance drug delivery, and the development of stimuli‐responsive nanoparticles offers more precise control over drug release. This study develops a novel all‐in‐one drug delivery system, using liposomes functionalized with a modified apolipoprotein E peptide (mApoE) for selectively targeting low‐density lipoprotein receptor (LDLR) overexpressed on tumor cells and a matrix metalloproteinase 2 (MMP2)‐cleavable lipopeptide. The bi‐functional liposomes are loaded with Pimasertib, a MAP/ERK kinase inhibitor (MEK1/2), and show enhanced delivery and effectiveness in reducing melanoma cell viability. Furthermore, these liposomes significantly decrease the growth and invasiveness of melanoma 3D spheroids and reduce the expression of epithelial‐to‐mesenchymal transition markers. These findings highlight the potential of MMP‐sensitive, mApoE‐functionalized liposomes as effective drug delivery systems for melanoma treatment, providing a promising approach for sustained drug release and targeted therapy in the tumor microenvironment. Moreover, this approach is promising not only for the treatment of melanoma but also for other types of tumors expressing LDLR and MMPs.