Organelle-targeted therapies: a comprehensive review on system design for enabling precision oncology

Abstract

Cancer is a major threat to human health. Among various treatment methods, precision therapy has received significant attention since the inception, due to its ability to efficiently inhibit tumor growth, while curtailing common shortcomings from conventional cancer treatment, leading towards enhanced survival rates. Particularly, organelle-targeted strategies enable precise accumulation of therapeutic agents in organelles, locally triggering organelle-mediated cell death signals which can greatly reduce the therapeutic threshold dosage and minimize side-effects. In this review, we comprehensively discuss history and recent advances in targeted therapies on organelles, specifically including nucleus, mitochondria, lysosomes and endoplasmic reticulum, while focusing on organelle structures, organelle-mediated cell death signal pathways, and design guidelines of organelle-targeted nanomedicines based on intervention mechanisms. Furthermore, a perspective on future research and clinical opportunities and potential challenges in precision oncology is presented. Through demonstrating recent developments in organelle-targeted therapies, we believe this article can further stimulate broader interests in multidisciplinary research and technology development for enabling advanced organelle-targeted nanomedicines and their corresponding clinic translations.

Fig. 1

Organelle-targeted therapy boosts cancer treatment outcomes by allowing for maximum accumulation of therapeutic agents in targets, triggering specific cell death pathways

Fig. 2

Timeline of the key advances in developing organelle-targeted therapies

Fig. 3

Design guidelines of nuclear-targeted nanosystems. Small cargoes cross the nuclear envelope through passive diffusion, without interaction with NPC. Active targeting is necessary for large cargoes. NLS-cargoes interact with nuclear transport receptors to achieve large cargoes accumulation in the nucleus. Nuclear envelope permeability enhancement allows ROS and mechanical forces to enhance the permeability of the nuclear envelope, and thus facilitate large cargo nuclear transportation. Nuclear pore expansion is a direct manner that dexamethasone regulates to expand the size of NPC. INM inner nuclear membrane, ONM outer nuclear membrane, NPC nuclear pore complexes, NLS nuclear localization signal, Impα importin α, Impβ importin β, RanGTP Ran guanosine triphosphate

Fig. 4

Personalized therapeutic strategies toward mitochondria. a The structure and function of mitochondria are displayed, with emphasis on the TCA cycle and β-oxidation. In contrast, cancer cells rely on the “Warburg effect” to achieve energy supply. b Mitochondrial dysfunctions to trigger cell death include metabolism disruption, redox state imbalance, and perturbation of mtDNA. Once mitochondrial damage and mPTP opening occur, cell death may occur by mitophagy, apoptosis, necroptosis, or ferroptosis. IMM inner mitochondrial membrane, OMM outer mitochondrial membrane, MM mitochondrial matrix, PDK dehydrogenase kinases, GAPDH glyceraldehyde 3-phosphate dehydrogenase, ROS reactive oxygen species, GSH glutathione, Cyt C cytochrome C

Fig. 5

The personalized therapeutic strategy toward lysosomes. a Lysosomes play a vital role in exocytosis, endocytosis, autophagy, and cell death. b LMP induction, as a typical approach, can be triggered by ROS, toxin reagents, radiation, and magnetic fields, eventually leading to caspase-dependent cell death. Proton pump inhibition is another strategy that enables overcoming MDR. Furthermore, HSP70 inhibition and iron release increase sensitivity to lysosomal-dependent cell death (LDCD). LMP lysosomal membrane permeabilization, ROS reactive oxygen species, Cyt C cytochrome c, PPI proton pump inhibitors, HSP 70 heat shock protein 70

Fig. 6

Unfolded protein response (UPR) is a valuable target in cell death. Protein misfolding or unfolded can occur as a disturbance in ER homeostasis, leading to ER stress. Chemotherapeutic agents, ROS, proteasome inhibitors, and HSP 90 inhibitors as ER stress inducers perturb ER homeostasis differently. If ER stress is not resolved in a timely fashion, unfolded or misfolded proteins accumulate in ER, and UPR triggers cell death via ATF6, PERK and IRE1α mediated signaling pathways. Importantly, fluctuations in ER and mitochondrial Ca²⁺ homeostasis can initiate mitochondrial-mediated cell death. UPR unfolded protein response, ROS reactive oxygen species, HSP 90 heat shock protein 90, mPTP mitochondrial permeability transition pore, CHOP C/EBP homologous protein, ATF6 p50ATF60, ATF4 transcription factor 4, TRAF2 TNF receptor-associated factor 2, ASK1 apoptosis signal-regulating kinase 1, JNK c-jun N-terminal kinase