Targeted nanomedicines for endoplasmic reticulum stress: organelle-resolved delivery, immune modulation, and genetic reprogramming.

Abstract

Endoplasmic reticulum stress (ERS) and the unfolded protein response (UPR) operate as central signaling hubs that integrate cellular homeostasis, adaptation, and fate determination. Dysregulation of this network constitutes a common pathogenic thread across cancer, metabolic syndromes, neurodegeneration, and inflammatory disorders. Although small molecule ERS modulators have validated the therapeutic relevance of this axis, their clinical translation remains constrained by intrinsic pharmacokinetic limitations, including poor solubility, off-tissue distribution, and an inability to synchronize drug action with the fluctuating dynamics of ERS. Nanotechnology is now catalyzing a paradigm shift by which engineered nanocarriers do not merely deliver ERS-targeting agents more efficiently; they unlock entirely new modalities of ERS intervention. By integrating stimuli-responsive motifs responsive to pH, reactive oxygen species, or enzymes, nanocarriers enable spatiotemporally programmable release that aligns therapeutic action with disease microenvironments. Through surface engineering and subcellular tropism, they achieve organelle-resolved ERS calibration, directing cargoes to the endoplasmic reticulum, mitochondria, or Golgi apparatus to modulate stress at its source. Beyond subcellular compartments, nanocarriers can also be tailored to target specific immune subsets, enabling precise modulation of ERS in dendritic cells, macrophages, and T lymphocytes. This emerging capability provides a means to reshape antigen presentation, inflammatory polarization, and effector functions, thereby linking ERS biology to cancer immunotherapy, autoimmune regulation, and infectious disease control. When integrated with epigenetic modulation, nanocarrier-mediated co-delivery of genetic and epigenetic agents offers a convergent strategy to simultaneously reprogram UPR signaling and correct epigenetic aberrations, thereby achieving superior therapeutic outcomes in ERS-driven diseases compared with single-modality approaches. This review systematically dissects nanocarrier-enabled strategies for ERS modulation, with emphasis on their architectural innovations in drug delivery, molecular logic of intervention, and therapeutic applications across major disease models. We also discuss current barriers to clinical translation and highlight emerging directions for extending ERS-targeted interventions toward broader pathological contexts.