Luminescent nanoparticles (LNPs) have emerged as a promising approach for enhanced cell labelling and disease diagnosis by leveraging their unique photophysical and surface characteristics. Advanced generations of LNPs, such as quantum dots, dye-loaded nanoparticles and up-converting nanoparticles, exhibit distinct properties and advantages tailored for specialised applications. Consequently, there is a growing focus and demand to develop organelle-specific LNPs to identify, treat and elucidate disease mechanisms. The endoplasmic reticulum (ER) represents one such organelle, playing crucial roles in protein synthesis and modification, calcium homeostasis, lipid trafficking, and regulation of cellular stress. The unfolded protein response, regulated by ER stress, is a clinically significant pathway within the ER, implicated in cellular dysfunction and disease. The growing understanding of ER stress and the unfolded protein response has led to a rapid emergence of endoplasmic reticulum-targeting LNPs (ER-LNPs) for precise intracellular diagnosis and therapy. This review discusses current advances and design principles of ER-LNPs, highlights current achievements and applications, and discusses the challenges and interdisciplinarity needed for future development.