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In order to meet the joint loading of two drugs with different physicochemical properties without affecting each other, an oral Janus nanoparticle (JNP) with a unique cavity structure and synergistic drug delivery was constructed using an improved double emulsion solvent evaporation method, and combined with low-molecular-weight chitosan\/sodium alginate and PLGA to achieve its pH-responsive.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The synthesized \u03b1CT\/Res-JNPs are homogeneous in shape, with a two-compartment structure, approximately 230\u00a0nm in size, and zeta potential of 23.6\u00a0mV. Drug release assayed in vitro show that JNP was stable in simulated gastric juice (pH\u2009=\u20091.2) but was released in phosphate buffer saline (pH\u2009=\u20097.4). After intragastric administration in rats, PK evaluation showed that \u03b1CT\/Res-JNPs could significantly improve the oral bioavailability, and the simultaneous encapsulation of the two drugs had no significant interaction on PK parameters. An obvious synergistic analgesic effects of \u03b1CT\/Res-JNPs was confirmed in a spinal cord injury and acute pain model. Confocal laser scanning microscopy and single-pass intestinal perfusion model provided strong evidence that \u03b1CT\/Res-JNPs could pass through intestinal epithelial cells, and the endocytosis pathway was mainly involved in the mediation and pinocytosis of reticulin. The concentrations of \u03b1CT and Res from \u03b1CT\/Res-JNP in lymphatic transport were only about 8.72% and 6.08% of their blood concentrations at 1\u00a0h, respectively, which indicated that lymphatic transport in the form of JNP has limited advantages in improving the oral bioavailability of Res and \u03b1CT. Cellular uptake efficiency at 4\u00a0h was about 10\u201315% in Caco-2 cell lines for \u03b1CT\/Res-JNP, but was reduced to 7% in Caco-2\/HT29-MTX co-culture models due to the hindrance by the mucus layers. Approximately 12\u201317% of \u03b1CT\/Res-JNP were transported across Caco-2\/HT29-MTX\/Raji monolayers. The cumulative absorption of JNP in three cell models was higher than that of free drug.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study investigated the contribution of Janus nanoparticles in oral absorption, and provide a new perspective for oral administration and analgesic treatment of dual drug delivery system containing peptide drugs.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Graphic Abstract<\/jats:title>\n                  <\/jats:sec>","DOI":"10.1186\/s12951-021-00974-6","type":"journal-article","created":{"date-parts":[[2021,8,6]],"date-time":"2021-08-06T09:06:57Z","timestamp":1628240817000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["pH-sensitive dual drug loaded janus nanoparticles by oral delivery for multimodal analgesia"],"prefix":"10.1186","volume":"19","author":[{"given":"Lin","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendong","family":"Yao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaowei","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianqing","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1001-0160","authenticated-orcid":false,"given":"Xiaoyang","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,8,6]]},"reference":[{"key":"974_CR1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.h532","volume":"350","author":"MC Reid","year":"2015","unstructured":"Reid MC, Eccleston C, Pillemer K. 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