Hypothesized-Synergistic Mechanism of ASO-Mediated lncRNA Targeting and miRNA-125b Modulation Using PEGylated Alginate-Chitosan Nanoparticles in SCC

Abstract

Non-melanoma skin cancer squamous cell carcinoma (NMSC-SCC) represents a growing clinical burden, particularly among coastal populations with prolonged UV exposure. Despite available surgical and systemic therapies, current approaches lack molecular specificity and multitarget efficacy. Long non-coding RNAs (lncRNAs) HOTAIR and ANRIL have been identified as oncogenic drivers in SCC through epigenetic silencing of tumor suppressor genes via Polycomb Repressive Complex 2 (PRC2) and activation of the Hedgehog (Hh) signaling pathway. Concurrently, miRNA-125b functions as a tumor suppressor by downregulating BCL-2 and BMI1, both of which are promoted by HOTAIR and ANRIL overexpression. Antisense oligonucleotides (ASOs) offer a promising RNA-targeting strategy capable of degrading lncRNA transcripts via RNase H-mediated cleavage and sterically blocking translational machinery. However, effective intracellular delivery remains a major challenge. This review proposes a novel delivery platform, PEG-modified alginate-chitosan nanoparticles (PEG-CANPs) derived from Macrocystis pyrifera brown algae, to encapsulate ASOs targeting HOTAIR and ANRIL, while synergistically modulating miRNA-125b expression. The ionotropic gelation method enables efficient encapsulation with high stability under acidic conditions, supporting transdermal delivery to skin cancer lesions. Evidence from prior studies demonstrates that ASO-modified CANPs effectively suppress BCL-2 and c-MET in breast cancer models, supporting their translational potential. This review synthesizes current molecular evidence and proposes a mechanistic framework for the synergistic multi-target approach in NMSC-SCC. Further preclinical studies are warranted to validate efficacy and safety.