Mesoporous silica nanoparticles with chiral pattern topological structure function as“antiskid tires”on the intestinal mucosa to facilitate oral drugs delivery

The weak adhesion between nanocarriers and the intestinal mucosa was one of the main reasons caused the failure in oral delivery.Inspired by the“antiskid tires”with complex chiral patterns,mesoporous silica nanoparticles AT-R@CMSN exhibiting geometrical chiral structure were designed to improve the surface/interface roughness in nanoscale,and employed as the hosting system for insoluble drugs nimesulide(NMS)and ibuprofen(IBU).Once performing the delivery tasks,AT-R@CMSN with rigid skeleton protected the loaded drug and reduced the irritation of drug on gastrointestinal tract(GIT),while their porous structure deprived drug crystal and improved drug release.More importantly,AT-R@CMSN functioned as“antiskid tire”to produce higher friction on intestinal mucosa and substantively influencedmultiple biological processes,including“contact”,“adhesion”,“retention”,“permeation”and“uptake”,compared to the achiral S@MSN,thereby improving the oral adsorption effectiveness of such drug delivery systems.By engineering AT-R@CMSN to overcome the stability,solubility and permeability bottlenecks of drugs,orally administered NMS or IBU loaded AT-R@CMSN could achieve higher relative bioavailability(705.95%and 444.42%,respectively)and stronger anti-inflammation effect.In addition,AT-R@CMSN displayed favorable biocompatibility and biodegradability.Undoubtedly,the present finding helped to understand the oral adsorption process of nanocarriers,and provided novel insights into the rational design of nanocarriers.

Lyophilized lymph nodes:A paradigm shift in CAR T-cell delivery for solid tumor therapy

CAR T(chimeric antigen receptor T-cell)therapy represents a paradigm shift in cancer treatments.By empowering immune cells to target malignant cells directly,it opens another door to precision medicine,promising cures for once refractory malignancies.However,the extension of CAR T therapy to solid tumors confronts formidable obstacles1.The physical and biochemical barriers within the tumor microenvironment,such as dense extracellular matrices and immunosuppressive factors,impede CAR T cell infiltration and function,leading to diminished success rates in solid tumor treatment2.

Chiral mesoporous silica nano-screws as an efficient biomimetic oral drug delivery platform through multiple topological mechanisms

In the microscale, bacteria with helical body shapes have been reported to yield advantages in many bio-processes. In the human society, there are also wisdoms in knowing how to recognize and make use of helical shapes with multi-functionality. Herein, we designed atypical chiral mesoporous silica nano-screws(CMSWs) with ideal topological structures(e.g., small section area, relative rough surface,screw-like body with three-dimension chirality) and demonstrated that CMSWs displayed enhanced bioadhesion, mucus-penetration and cellular uptake(contributed by the macropinocytosis and caveolaemediated endocytosis pathways) abilities compared to the chiral mesoporous silica nanospheres(CMSSs)and chiral mesoporous silica nanorods(CMSRs), achieving extended retention duration in the gastrointestinal(GI) tract and superior adsorption in the blood circulation(up to 2.61-and 5.65-times in AUC).After doxorubicin(DOX) loading into CMSs, DOX@CMSWs exhibited controlled drug release manners with pH responsiveness in vitro. Orally administered DOX@CMSWs could efficiently overcome the intestinal epithelium barrier(IEB), and resulted in satisfactory oral bioavailability of DOX(up to 348%).CMSWs were also proved to exhibit good biocompatibility and unique biodegradability. These findings displayed superior ability of CMSWs in crossing IEB through multiple topological mechanisms and would provide useful information on the rational design of nano-drug delivery systems.