Pancreatic fibrosis (PF) is primarily distinguished by the stimulation of pancreatic stellate cells (PSCs) and excessive extracellular matrix deposition, which is the main barrier impeding drug delivery and distribution. Recently, nanomedicine, with efficient, targeted, and controllable drug release characteristics, has demonstrated enormous advantages in the regression of pancreas fibrotic diseases. Notably, paracrine signals from parenchymal and immune cells such as pancreatic acinar cells, islet cells, pancreatic cancer cells, and immune cells can directly or indirectly modulate PSC differentiation and activation. The intercellular crosstalk between PSCs and these cells has been a critical event involved in fibrogenesis. However, the connections between PSCs and other pancreatic cells during the progression of diseases have yet to be discussed. Herein, we summarize intercellular crosstalk in the activation of PSCs and its contribution to the development of common pancreatic diseases, including pancreatitis, pancreatic cancer, and diabetes. Then, we also examine the latest treatment strategies of nanomedicine and potential targets for PSCs crosstalk in fibrosis, thereby offering innovative insights for the design of antifibrotic nanomedicine. Ultimately, the enhanced understanding of PF will facilitate the development of more precise intervention strategies and foster individually tailored therapeutic approaches for pancreatic diseases.

Leber's hereditary optic neuropathy (LHON) is an ocular mitochondrial disease that involves the impairment of mitochondrial complex I, which is an important contributor to blindness among young adults across the globe. However, the disorder has no available cures, since the approved drug idebenone for LHON in Europe relies on bypassing complex I defects rather than fixing them. Herein, PARKIN mRNA-loaded nanoparticle (mNP)-engineered mitochondria (mNP-Mito) were designed to replace dysfunctional mitochondria with the delivery of exogenous mitochondria, normalizing the function of complex I for treating LHON. The mNP-Mito facilitated the supplementation of healthy mitochondria containing functional complex I via mitochondrial transfer, along with the elimination of dysfunctional mitochondria with impaired complex I via an enhanced PARKIN-mediated mitophagy process. In a mouse model induced with a complex I inhibitor (rotenone, Rot), mNP-Mito enhanced the presence of healthy mitochondria and exhibited a sharp increase in complex I activity (76.5%) compared to the group exposed to Rot damage (29.5%), which greatly promoted the restoration of ATP generation and mitigation of ocular mitochondrial disease-related phenotypes. This study highlights the significance of nanoengineered mitochondria as a promising and feasible tool for the replacement of dysfunctional mitochondria and the repair of mitochondrial function in mitochondrial disease therapies.

Liver fibrosis is a major disease that affects human health. Currently,drugs used for the treatment of hepatic fibrosis have such problems as low drug solubility,lack of liver specificity and possible occurrence of side-effects. In order to improve the anti-fibrosis therapeutic efficacy,various nano-drug delivery systems and targeting strategies are explored in liver fibrosis therapy. This review summarizes the drug delivery systems and targeting strategies that have been applied to liver fibrosis therapy in recent years from the types of carriers and modified ligands,which serve as a basis of designing safe and effective drug delivery systems for liver fibrosis therapy.

Biodegradable polyamines have long been studied as potential recombinant viral gene vectors. Spermine (SPE) is an endogenous tetra-amine with excellent biocompatibility yet poor gene condensation capacity. We have previously synthesized a polyspermine based on SPE and poly(ethylene glycol) (PEG) diacrylate (SPE-alt-PEG) for enhanced transfection performance, but the synthesized SPE-alt-PEG still lacked specificity towards cancer cells. In this study, folic acid (FA) was incorporated into SPE-alt-PEG to fabricate a targeted gene delivery vector (FA-SPE-PEG) via an acylation reaction. FA-SPE-PEG exhibited mild cytotoxicity in both cancer cells and normal cells. FA-SPE-PEG possessed higher transfection efficiency than PEI 25 K and Lipofectamine(®) 2000 in two tested cancer cell lines at functional weight ratios, and its superiority over untargeted SPE-alt-PEG was prominent in cells with overexpressed folate receptors (FRs). Moreover, in vivo delivery of green fluorescent protein (GFP) with FA-SPE-PEG resulted in highest fluorescent signal intensity of all investigated groups. FA-SPE-PEG showed remarkably enhanced specificity towards cancer cells both in vivo and in vitro due to the interaction between FA and FRs. Taken together, FA-SPE-PEG was demonstrated to be a prospective targeted gene delivery vector with high transfection capacity and excellent biocompatibility.

The mitochondria-targeted TPP-PEI-LND was synthesized by mitochondria-targeted ligand triphenylphosphine(TPP)and therapeutic drug lonidamine(LND)conjugated to low molecular weight branched polyethyleneimine(PEI). TPP-PEI-LND was verified using 1H NMR; in vitro release was determined by the dialysis. Besides, the cytotoxicity and mitochondria-targeted potential of TPP-PEI-LND were investigated in HeLa cells. The results showed that TPP-PEI-LND was successfully synthesized and it exhibited the feature of extended-release. Hence, TPP-PEI-LND could deliver LND to mitochondria, resulting in significantly enhanced efficacy of LND.