Self-Assembled Nanomaterials for ER-Targeted Cancer Therapy: From Molecular Design to Therapeutic Applications

The endoplasmic reticulum (ER) is essential for protein folding, lipid metabolism, calcium homeostasis, and cellular stress signaling. Cancer cells endure chronic ER stress from elevated metabolic demands and oxidative conditions, adapting ER pathways to evade apoptosis, while promoting growth, survival, and drug resistance. This dysregulated ER state presents a strategic therapeutic target. Self-assembled nanomaterials provide precise ER localization, significantly enhancing treatment efficacy while reducing systemic toxicity. This review details recent advances in their design for ER-targeted cancer therapy, focusing on in situ assembly (stimulus-driven intracellular formation) and preassembled nanostructures constructed from peptides, polymers, and small molecules. Therapeutic applications encompass chemotherapy, photodynamic therapy, bioimaging, immunotherapy, and nanovaccines. Key challenges to clinical translation─including in vivo delivery efficiency, targeting specificity, and regulatory requirements─are thoroughly examined, alongside promising directions in programmable, multiorganelle-targeting, and bioresponsive nanomedicines. By integration of self-assembly principles with ER stress biology, these platforms establish a robust foundation for precise, patient-tailored cancer therapies.