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Traditionally, herbal medicine is consumed by drinking decoctions produced by boiling herbs with water. The functional components of the decoction are heat stable. Small RNAs (sRNAs) were reported as a new class of functional components in decoctions. However, the mechanisms by which sRNAs survive heat treatment of the decoction and enter cells are unclear. Previous studies showed that plant-derived exosome-like nanoparticles (ELNs), which we call botanosomes, could deliver therapeutic reagents in vivo. Here, we report that heat-stable decoctosomes (ELNs) from decoctions have more therapeutic effects than the decoctions in vitro and demonstrate therapeutic efficacy in vivo. Furthermore, sRNAs, such as HJT-sRNA-m7 and PGY-sRNA-6, in the decoctosome exhibit potent anti-fibrosis and anti-inflammatory effects, respectively. Decoctosome is comprised of lipids, chemical compounds, proteins, and sRNAs. A medical decoctosome mimic is called bencaosome. A single lipid sphinganine (d22:0) identified in the decoctosome was mixed and heated with the synthesized sRNAs to form the simplest bencaosome. This simple bencaosome structure was identified by critical micelle concentration (cmc) assay that sRNAs coassembled with sphinganine (d22:0) to form the lipid layers of vesicles. The heating process facilitates co-assembly of sRNAs and sphinganine (d22:0) until a steady state is reached. The artificially produced sphinganine-HJT-sRNA-m7 and sphinganine- PGY-sRNA-6 bencaosomes could ameliorate bleomycin-induced lung fibrosis and poly(I:C)-induced lung inflammation, respectively, following oral administration in mice. Our study not only demonstrates that the herbal decoctosome may represent a combinatory remedy in precision medicine but also provides an effective oral delivery route for nucleic acid therapy.

Pulmonary fibrosis, a progressive chronic disease with a high mortality rate, has limited treatment options. Currently, lung transplantation remains the only effective treatment. Here we report that a small RNA, HJT-sRNA-m7, from a Chinese herbal medicine Hong Jing Tian (HJT, RHODIOHAE CRENULATAE RADIX ET RHIZOMA, Rhodiola crenulata) can effectively reduce the expressions of fibrotic hallmark genes and proteins both in alveolar in vitro and in mouse lung tissues in vivo. We also discovered over one hundred oil-soluble chemicals from HJT decoctions, most of which are found in lipid extracts from other Chinese herbals decoctions, including Pu Gong Ying (PGY, TARAXACI HERBA, Taraxacum mongolicum), Chuan Xin Lian (CXL, changed to "ANDROGRAPHIS HERBA, Andrographis paniculata"), and Jin Yin Hua (JYH, lonicera japonica or Honeysuckle). We identified the active component in these decoctions as two forms of phosphocholines, PC (18:0/18:2) and PC (16:0/18:2). These PCs potentially could form liposomes with small RNAs to enter human alveolar and gastric cells. Our experimental results suggest an unprecendent lipid complex route through which botanic small RNA can enter human bodies. Our results provide an innovative treatment strategy for oral delivery of siRNAs as therapeutic medication.

Following the published article, we noticed an error duplication in Figure 5G "control" and "PGY-6" that was introduced during the revised process, with an attempt to replace it with higher-resolution images. Here we provide the original data in the first submitted manuscript (Figure 5G).