LPA_(1) antagonist-derived LNPs deliver A20 mRNA and promote anti-fibrotic activities

Activated fibroblasts are major mediators of pulmonary fibrosis.Fibroblasts are generally found in the connective tissue but upon activation can generate excess extracellular matrix(ECM)in the lung interstitial section.Therefore,fibroblasts are one of the most targeted cells for treating idiopathic pulmonary fibrosis(IPF).Here,we develop an anti-fibrotic platform that can modulate both the lysophosphatidic acid receptor 1(LPA_(1))and the inflammatory pathway through tumor necrosis factorα-induced protein 3(TNFAIP3,also known as A20)in fibroblasts.First,we synthesized a series of LPA_(1) antagonists,AM095 and AM966,derived amino lipids(LA lipids)which were formulated into LA-lipid nanoparticles(LA-LNPs)encapsulating mRNA.Specifically,LA5-LNPs,with AM966 head group and biodegradable acetal lipid tails,showed efficient A20 mRNA delivery to lung fibroblasts in vitro(80.2%±1.5%)and ex vivo(17.2%±0.4%).When treated to primary mouse lung fibroblasts(MLF),this formulation inhibited fibroblast migration and collagen production,thereby slowing the progression of IPF.Overall,LA5-LNPs encapsulated with A20 mRNA is a novel platform offering a potential approach to regulate fibroblast activation for the treatment of IPF.

Co-delivery of mRNA and SPIONs through amino-ester nanomaterials

Nanoparticles have been widely explored for combined therapeutic and diagnostic applications. For example, lipid-based nanoparticles have been used to encapsulate multiple types of agents and achieve multi-functions. Herein, we enabled a co-delivery of mRNA molecules and superparamagnetic iron oxide nanoparticles （SPIONs） by using an amino-ester lipid-like nanomaterial. An orthogonal experimental design was used to identify the optimal formulation. The optimal formulation, MPA-Ab-8 LLNs, not only showed high encapsulation of both mRNA and SPIONs, but also increased the r2 relaxivity of SPIONs by more than 1.5-fold in vitro. MPA-Ab-8 LLNs effectively delivered mRNA and SPIONs into cells, and consequently induced high protein expression as well as strong MRI contrast. Consistent herewith, we observed both mRNA-mediated protein expression and an evident negative contrast enhancement of MRI signal in mice. In conclusion, amino-ester nanomaterials demonstrate great potential as delivery vehicles for theranostic applications.

Chemotherapy drugs derived nanoparticles encapsulating mRNA encoding tumor suppressor proteins to treat triple-negative breast cancer

Triple-negative breast cancer(TNBC)is one type of the most aggressive breast can cers with poor prog no sis.It is of great urgency to develop new therapeutics for treati ng TNBC.Based on curre nt treatment guideline and genetic informatio n of TNBC,a combi nation al therapy platform in tegrati ng chemotherapy drugs and mRNA encoding tumor suppressor proteins may become an efficacious strategy.In this study,we developed paclitaxel amino lipid(PAL)derived nanoparticles(NPs)to incorporate both chemotherapy drugs and P53 mRNA.The PAL P53 mRNA NPs showed superior properties compared to Abraxane? and Lipusu? used in the clinic including high paclitaxel loading capacity(24 wt.%,calculated by paclitaxel in PAL),PAL encapsulation efficiency(94.7%±6.8%)and mRNA encapsulation efficiency(88.7%±0.7%).Meanwhile,these NPs displayed synergetic cytotoxicity of paclitaxel and P53 mRNA in cultured TNBC cells.More importantly,we demonstrated in vivo anti-tumor efficacy of PAL P53 mRNA NPs in an orthotopic TNBC mouse model.Overall,these chemotherapy drugs derived mRNA NPs provide a new platform to integrate chemotherapy and personalized medicine using tumor genetic information,and therefore represent a promising approach for TNBC treatment.