Beyond Nanoparticle-Based Intracellular Drug Delivery: Cytosol/Organelle-Targeted Drug Release and Therapeutic Synergism

Nanoparticle (NP)-based drug delivery systems are conceived to solve poor water-solubility and chemical/physical instability, and their purpose expanded to target specific sites for maximizing therapeutic effects and minimizing unwanted events of payloads. Targeted sites are also narrowed from organs/tissues and cells to cytosol/organelles. Beyond specific site targeting, the particular release of payloads at the target sites is growing in importance. This review overviews various issues and their general strategies during multiple steps, from the preparation of drug-loaded NPs to their drug release at the target cytosol/organelles. In particular, this review focuses on current strategies for "first" delivery and "later" release of drugs to the cytosol or organelles of interest using specific stimuli in the target sites. Recognizing or distinguishing the presence/absence of stimuli or their differences in concentration/level/activity in one place from those in another is applied to stimuli-triggered release via bond cleavage or nanostructural transition. In addition, future directions on understanding the intracellular balance of stimuli and their counter-stimuli are demonstrated to synergize the therapeutic effects of payloads released from stimuli-sensitive NPs. Organelle-targeted delivery and release can maximize therapeutic effects and minimize unwanted effects. In addition, when triggering the release of payloads from nanosized drug delivery systems, spending stimulus in the target organelle can create an imbalance of intracellular regulators (e.g., redox), resulting in synergism in therapeutic outcomes. image