**6. Conclusions and Future Perspectives**

This review summarizes the strategies being used to develop novel methods for the treatment of liver fibrosis on the basis of multifunctional NPs. The application of nanomedicine systems in the diagnosis and treatment of liver fibrosis is widely reported in the literature and continues to be a rapidly growing research field, with emphasis on active targeted drug delivery and theranostics. Numerous types of inorganic and organic NPs have been extensively investigated, including metal oxide NPs, metal NPs, liposomes, polymer NPs, dendrimers, protein NPs, and organic–inorganic hybrid NPs. Each type has its advantages disadvantages. Inorganic NPs are intrinsically robust with relatively low manufacturing costs, but their design flexibility and functionality are limited. Organic NPs possess broad design flexibility for integrating multiple functions into one platform but show structural instability and involve high manufacturing cost and fabrication complexity. Organic–inorganic hybrid NPs combine the advantages of organic NPs and inorganic NPs and thus are preferred in the development of theranostic platforms.

Although NPs have shown great potential for liver fibrosis therapy, they also exhibit hepatotoxicity [110–114]. The long-term hepatotoxicity of NPs should be carefully and systemically evaluated, particularly when they are used in patients with liver disease. Patients are more sensitive to NPs because of reduced self-protective mechanisms, decreased immune function, and lack of ability for self-repair. Studies have shown that exposure to NPs increases pathological damage [115–117]. Therefore, the health risks involved in the use of NPs for liver fibrosis therapy should be given significant attention.

Until now, lipid-based NPs were the only nanomedicine system that in the clinical stages of studies for the treatment of liver fibrosis. Lipid NPs delivering siRNA against heat shock protein 47 were developed to target HSCs and treat advanced liver fibrosis caused by NASH or hepatitis C virus infection. This nanomedicine system was in clinical phase 1b/2 and study results were safe and effective [118,119]. To improve the clinical applicability of nanomedicine systems in the future, the following directions should be considered: (1) Developing stimuli-responsive nanomedicine

systems with high sensitivity, which can intelligently respond to endogenous or exogenous stimuli and release payload at targeting sites. (2) Employing an "all-in-one" strategy to develop smart nanomedicine systems that combine multiple functionalities, including targeted delivery, prolonged blood retention, enhanced tissue penetration and cellular internalization, responsiveness to stimuli, and disease progressive monitoring. (3) Systematic evaluation of long-term toxicity, immunogenicity, and pharmacokinetics of medicine systems. Notably, from the clinical use of the reported nanomedicine systems, only one example was performed. All obstacles should be overcome by designing and fabricating nanomedicine systems with appropriate components, surface chemistry, sizes, payloads, and specific target ligands before clinical translation.

**Author Contributions:** X.B., G.S. and S.Z. designed this work of review. X.B. and G.S. performed the literature search of the databases. X.B. and G.S. wrote the manuscript. G.S. and S.Z. revised the manuscript. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Acknowledgments:** This research was funded by the National Natural Science Foundation of China (21677090, 22076085).

**Conflicts of Interest:** The authors declare no conflict of interest.
