Nanocrystals‐Based Drug Delivery for Hepatic Diseases: From Drug Selection to Kupffer Cell and Hepatocyte Targeting

ABSTRACT

Liver diseases (LD) are a global health concern that arises due to limitations of conventional therapies, including low solubility in biological fluids, rapid metabolism, and insufficient hepatic concentrations. However, nanocrystals (NCs) composed of pure active pharmaceutical ingredients (APIs) are emerging as the most effective tool for increasing the solubility, bioavailability, and targeting of poorly soluble drugs for LD. This review summarizes recent advances in the design, processing, and application of NCs for LD. The review focuses particularly on comparing top‐down, bottom‐up, and combined processing methods, with special consideration given to API‐specific requirements as a drug selection criterion for NCs, the choice of stabilizers, and the application of NCs in LD. The idea is to present polysaccharide‐based, inorganic, and drug NCs for targeting hepatocytes, kupffer cells, or hepatic stellate cells (HSC). Despite these promising advances, challenges including nonspecific sequestration by Kupffer cells, physical instability during storage, and limited clinical translation continue to restrict the therapeutic potential of nanocrystal‐based liver drug delivery systems. Further novel perspectives, such as artificial intelligence‐assisted preparation, liver‐on‐a‐chip technology, and Quality by Design approaches, are presented to develop NCs more comprehensively toward precision nanomedicines for treating liver fibrosis, hepatitis, or hepatic cancer.