Advances in siRNA delivery for breast cancer therapy: from molecular design to therapeutic application.

Abstract

Breast cancer progression is driven by molecular heterogeneity, drug resistance (DR), and interactions within the tumour microenvironment (TME), creating an urgent need for therapies that can selectively suppress disease-associated genes. Small interfering RNA (siRNA) can silence targets involved in tumour growth, treatment resistance, and immune evasion. Its therapeutic potential, however, depends on overcoming rapid degradation and clearance, limited tumour accumulation, poor cellular uptake, and endosomal entrapment. Lipid-based and polymer-mediated delivery systems (DS) protect siRNA and facilitate its transport, while chemical modifications, molecular conjugates, and physical delivery methods offer additional ways to improve stability or access to target cells. In BC models, these strategies have been investigated for targeted therapy, reversal of DR, and modulation of the TME to support antitumor immunity. Despite encouraging preclinical findings, effective tumour delivery, sustained gene silencing, off-target effects, and immune activation remain significant barriers to clinical translation. This review brings together advances in siRNA delivery and their applications against BC progression, DR, and immune evasion, while defining the barriers that must be overcome to translate effective gene silencing into meaningful clinical benefit.

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