Microenvironment-guided design of non-viral gene delivery systems: from biological cues to therapeutic translation

Non-viral gene delivery systems offer adaptable alternatives to viral vectors for gene therapy. Nevertheless, their clinical translation remains limited by biological barriers and the pathological tissue microenvironment. Tumors exhibit alterations in the tissue microenvironment, including extracellular acidosis, altered redox balance, elevated reactive oxygen species (ROS), dysregulated enzymatic activity, and hypoxia, which can serve as endogenous cues for designing stimulus-responsive gene delivery systems with site-specific cargo release.

This narrative review examines tumor microenvironment-responsive non-viral gene delivery systems and discusses how disease-specific biological cues can be integrated into carrier design. We distinguish disease-associated tissue cues from intracellular triggers such as endosomal acidification and evaluate how these stimuli influence carrier stability, cellular interactions, intracellular trafficking, and therapeutic efficacy, while considering trade-offs in sensitivity, specificity, safety, and manufacturability. Relevant literature was identified through PubMed, Scopus, and Web of Science for English-language studies published between 2010 and 2026.

Emphasizing the transition from material-driven approaches toward biology-guided design, this review proposes an integrated decision framework to guide the design and translational evaluation of microenvironment-responsive non-viral gene delivery systems. It highlights translation challenges, including microenvironmental heterogeneity, manufacturing and scalability challenges, and safety and regulatory considerations.