Strategies for endoplasmic reticulum-targeted delivery systems: current design principles and trends

INTRODUCTION: The endoplasmic reticulum (ER) governs proteostasis, lipid biosynthesis, calcium signaling, stress responses, and antigen presentation, making it an attractive yet challenging intracellular target for therapeutic delivery. AREAS COVERED: PubMed and Google Scholar were searched, with ER-targeting literature limited to January 2024-August 2026; no date limit was applied to foundational ER biology. We compare small-molecule motifs, peptide signals, biomimetic membranes, lipid-based formulations, physicochemical trafficking cues, and enzyme-instructed self-assembly, with particular attention to stimulator of interferon genes (STING) agonist-based ER-targeting molecules (SABER), palmitic-acid-mediated trafficking, shape-engineered exosome-membrane-coated nanorods, ER-tropic polymers, and retrograde sorting combined with ER retention. A four-level evidence framework for ER-targeting claims is proposed, alongside cargo-specific design, safety, manufacturability, and translational considerations. EXPERT OPINION: Among recent strategies, SABER has the most complete evidence for a defined protein-ligand ER docking interaction, although the docking protein is itself pharmacologically active and dynamically trafficked, which constrains both generalizability and the interpretation of ER residence. Near-term progress is more likely to come from matching validated targeting motifs to appropriate cargos and quantifying the entire delivery pathway than from increasingly elaborate nanocarrier designs. Clinically viable systems will require non-perturbing ligands, human-relevant validation models, biodegradable formulations, and biomarkers predictive of ER exposure and therapeutic response.