Brucea javanica derived exosome-like nanovesicles deliver miRNAs for cancer therapy.

Triple-negative breast cancer (TNBC) is characterized by complex heterogeneity, high recurrence and metastasis rates, and short overall survival, owing to the lack of endocrine and targeted receptors, which necessitates chemotherapy as the major treatment regimen. Exosome-like nanovesicles derived from medicinal plants have shown great potential as novel biotherapeutics for cancer therapy by delivering their incorporated nucleic acids, especially microRNAs (miRNAs), to mammalian cells. In this study, we isolated exosome-like nanovesicles derived from B. javanica (BF-Exos) and investigated their influence and underlying molecular mechanisms in TNBC. We found that BF-Exos delivered 10 functional miRNAs to 4T1 cells, significantly retarding the growth and metastasis of 4T1 cells by regulating the PI3K/Akt/mTOR signaling pathway and promoting ROS/caspase-mediated apoptosis. Moreover, BF-Exos were shown to inhibit the secretion of vascular endothelial growth factor, contributing to anti-angiogenesis in the tumor microenvironment. In vivo, BF-Exos inhibited tumor growth, metastasis, and angiogenesis in breast tumor mouse models, while maintaining high biosafety. Overall, BF-Exos are considered promising nanoplatforms for the delivery of medicinal plant-derived nucleic acids, with great potential to be developed into novel biotherapeutics for the treatment of TNBC.

Oriented artificial niche provides physical-biochemical stimulations for rapid nerve regeneration.

Skin wound is always accompanied with nerve damage, leading to significant sensory function loss. Currently, the functional matrix material based stem cell transplantation and in situ nerve regeneration are thought to be effective strategies, of which, how to recruit stem cells, retard senescence, and promote neural differentiation has been obstacle to be overcome. However, the therapeutic efficiency of the reported systems has yet to be improved and side effect reduced. Herein, a conduit matrix with three-dimensional ordered porous structures, regular porosity, appropriate mechanical strength, and conductive features was prepared by orienting the freezing technique, which was further filled with neural-directing exosomes to form a neural-stimulating matrix for providing hybrid physical-biochemical stimulations. This neural-stimulating matrix was then compacted with methacrylate gelatin (GelMA) hydrogel thin coat that loaded with chemokines and anti-senescence drugs, forming a multi-functional artificial niche (termed as GCr-CSL) that promotes MSCs recruitment, anti-senescence, and neural differentiation. GCr-CSL was shown to rapidly enhances in situ nerve regeneration in skin wound therapy, and with great potential in promoting sensory function recovery. This study demonstrates proof-of-concept in building a biomimetic niche to organize endogenous MSCs recruitment, differentiation, and functionalization for fast neurological and sensory recovery.

All-in-one smart dressing for simultaneous angiogenesis and neural regeneration.

Wound repair, along with skin appendage regeneration, is challenged by insufficient angiogenesis and neural regeneration. Therefore, promoting both proangiogenic and neuro-regenerative therapeutic effects is essential for effective wound repair. However, most therapeutic systems apply these strategies separately or ineffectively. This study investigates the performance of an all-in-one smart dressing (ASD) that integrates angiogenic functional materials and multiple biological factors within a light crosslinked hydrogel, forming a multi-functional dressing capable of facilitating simultaneous micro-vascularization and neural regeneration. The ASD uses a zeolite-imidazolate framework 67 with anchored vanadium oxide (VO2@ZIF-67) that allows for the on-demand release of Co2+ with fluctuations in pH at the wound site to stimulate angiogenesis. It can simultaneously release CXCL12, ligustroflavone, and ginsenoside Rg1 in a sustained manner to enhance the recruitment of endogenous mesenchymal stem cells, inhibit senescence, and induce neural differentiation to achieve in situ nerve regeneration. The ASD can stimulate rapid angiogenesis and nerve regeneration within 17 days through multiple angiogenic and neuro-regenerative cues within one dressing. This study provides a proof-of-concept for integrating functional nanomaterials and multiple complementary drugs within a smart dressing for simultaneous angiogenesis and neural regeneration.

ZIF@VO2 as an Intelligent Nano-Reactor for On-Demand Angiogenesis and Disinfection.

Absent angiogenesis and bacterial infection are two major challenges that simultaneously delay the repair of injured tissues and organs. However, most current therapeutic systems deliver therapeutic cues in a separate and inaccurate manner which stimulates angiogenesis or inhibits infection leading to limited repair and side effects. Advanced therapeutic systems capable of providing accurate angiogenic stimulation and anti-infection signals in response to the changing microenvironment are urgently needed. Herein, a nano-reactor (ZFVO) involving zeolitic imidazolate framework-67 (ZIF-67)-deposited hollow vanadium oxide (VO2 ) is developed to intelligently execute pro-angiogenesis and/or disinfection via the responsive release of cobalt ions and hydroxyl radicals to the injury and infection sites, respectively. ZFVO nano-reactor demonstrates a novel strategy for constructing drug-free nano-platforms with a hierarchical structure which has potential for the accurate treatment of trauma and orthopedic diseases.

Self-powered smart patch promotes skin nerve regeneration and sensation restoration by delivering biological-electrical signals in program.

Skin wound is always accompanied with nerve destruction. Due to the limited clinical treatment option, loss of skin sensation with unsatisfactory nerve regeneration is remained to be a challenge for wound therapy. Endogenous mesenchymal stem cells (MSCs) based in situ regeneration, of which, MSCs recruited by chemokines and directed for neuronal differentiation by biological and electrical signals have been thought a novel strategy with potential to accelerate the nerve regeneration and sensory functions recovery. However, most current therapeutic systems usually deliver the chemokines, biological and electrical signals separately and statically, resulting in limited nerve regeneration and sensory functions recovery. Moreover, most of the devices for providing electrical signals need external energy input and complicated practice, leading to poor compliance in patients. To address these issues, we propose a self-powered smart patch (PRG-G-C) to provide chemokine and biological-electrical cues in program. PRG-G-C was composed of a flexible piezoelectric generator to supply electrical stimulation and a conductive gel, which served as the reservoir of chemokine and neural directing exosomes as well as the electrode to transfer electric cue. PRG-G-C was shown to efficiently accelerate rapid nerve regeneration and sensation restoration at the wound site within 23 days. This study demonstrates a proof-to-concept in organizing chemokine, neural directing biological-electrical heterogeneous cues within a self-powered smart patch for accelarating nerve regeneration and sensation restoration, possessing great potential in neural repair applications.

Recent Advances in Intelligent Wearable Medical Devices Integrating Biosensing and Drug Delivery.

The primary roles of precision medicine are to perform real-time examination, administer on-demand medication, and apply instruments continuously. However, most current therapeutic systems implement these processes separately, leading to treatment interruption and limited recovery in patients. Personalized healthcare and smart medical treatment have greatly promoted research on and development of biosensing and drug-delivery integrated systems, with intelligent wearable medical devices (IWMDs) as typical systems, which have received increasing attention because of their non-invasive and customizable nature. Here, the latest progress in research on IWMDs is reviewed, including their mechanisms of integrating biosensing and on-demand drug delivery. The current challenges and future development directions of IWMDs are also discussed.

Smart graphene-based hydrogel promotes recruitment and neural-like differentiation of bone marrow derived mesenchymal stem cells in rat skin.

Strategies to direct the differentiation of endogenous bone marrow derived mesenchymal stem cells (BMSCs) in vivo following recruitment to the injured site are critical to realizing the potential of stem cell-based therapies. But the differentiation efficiency of BMSCs remains limited without direction. Here we demonstrated a novel strategy to promote neuronal differentiation of BMSCs using cross-linked polyethylenimine (PEI) grafted graphene oxide (GO) as the enzyme responsive vector for delivering active genes to BMSCs. In vivo, a core-shell microfiber arrayed hydrogel with a chemokine (SDF-1α) and the cross-linked GO-PEI/pDNAs-bFGF microparticles incorporated into the shell and core, respectively, were constructed. The arrayed hydrogel was shown to recruit and stimulate the neural-like differentiation of BMSCs effectively by delivering the CXCL12 and GO-PEI/pDNAs-bFGF in a self-controlled manner. With this strategy, both in vitro and in vivo neuronal differentiation of BMSCs with function were accelerated significantly. The cross-linked GO-PEI mediated gene transfection together with a multi-functional microfiber arrayed hydrogel provide a translatable approach for endogenous stem cell-based regenerative therapy.