ABSTRACT
Mesenchymal stem cells (MSCs) experience substantial viability issues in the stroke infarct region, limiting their therapeutic efficacy and clinical translation. High levels of deadly reactive oxygen radicals (ROS) and proinflammatory cytokines (PC) in the infarct milieu kill transplanted MSCs, whereas low levels of beneficial ROS and PC stimulate and improve engrafted MSCs' viability. Based on the intrinsic hormesis effects in cellular biology, we built a microglia-inspired MSC bioengineering system to transform detrimental high-level ROS and PC into vitality enhancers for strengthening MSC therapy. This system is achieved by bioorthogonally arming metabolic glycoengineered MSCs with microglial membrane-coated nanoparticles and an antioxidative extracellular protective layer. In this system, extracellular ROS-scavenging and PC-absorbing layers effectively buffer the deleterious effects and establish a micro-livable niche at the level of a single MSC for transplantation. Meanwhile, the infarct's inanimate milieu is transformed at the tissue level into a new living niche to facilitate healing. The engineered MSCs achieved viability five times higher than natural MSCs at seven days after transplantation and exhibited a superior therapeutic effect for stroke recovery up to 28 days. This vitality-augmented system demonstrates the potential to accelerate the clinical translation of MSC treatment and boost stroke recovery.
ABSTRACT
Tumor cell-derived cancer nanovaccines introduce tumor cell-derived components as functional units that endow the nanovaccine systems with some advantages, especially providing all potential tumor antigens. However, cumbersome assembly steps, potential risks of exogenous adjuvants, as well as insufficient lymph node (LN) targeting and dendritic cell (DC) internalization limit the efficacy and clinical translation of existing tumor cell-derived cancer nanovaccines. Herein, we introduced an endoplasmic reticulum (ER) stress inducer α-mangostin (αM) into tumor cells through poly(d, l-lactide-co-glycolide) nanoparticles and harvested biologically self-assembled tumor cell-derived cancer nanovaccines (αM-Exos) based on the biological process of tumor cell exocytosing nanoparticles through tumor-derived exosomes (TEXs). Besides presenting multiple potential antigens, αM-Exos inherited abundant 70 kDa heat shock proteins (Hsp70s) upregulated by ER stress, which can not only act as endogenous adjuvants but also improve LN targeting and DC internalization. Following subcutaneous injection, αM-Exos efficiently migrated to LNs and was expeditiously endocytosed by DCs, delivering tumor antigens and adjuvants to DCs synchronously, which then powerfully triggered antitumor immune responses and established long-term immune memory. Our study exhibited an all-in-one biologically self-assembled tumor cell-derived cancer nanovaccine platform, and the fully featured cancer nanovaccines assembled efficiently through this platform are promising for desirable cancer immunotherapy.
Subject(s)
Cancer Vaccines , Nanoparticles , Neoplasms , Humans , Nanovaccines , Antigens, Neoplasm , Immunotherapy , Dendritic CellsABSTRACT
Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. Long-term changes in the microenvironment of the brain contribute to the degeneration of neurological function following TBI. However, current research focuses primarily on short-term modulation during the early phases of TBI, not on the critical significance of long-term homeostasis in the brain microenvironment. Notably, dysfunction of the glymphatic-lymphatic system results in the accumulation of danger/damage-associated molecular patterns (DAMPs) in the brain, which is regarded as the leading cause of long-term microenvironmental disturbances following TBI. Here, a nanostructure, Nano-plumber, that co-encapsulates the microenvironment regulator pro-DHA and the lymphatic-specific growth factor VEGF-C is developed, allowing for a sustainable and orderly regulation of the microenvironment to promote long-term neurological recovery. Nano-plumber reverses the injury microenvironment by suppressing microglia and astrocytes activation and maintaining reduced activation via enhanced glymphatic-lymphatic drainage, and significantly improves the neurological function of rodents with TBI. This study demonstrates that glymphatic-lymphatic system reconstruction is essential for enhancing long-term prognosis following TBI, and that the Nano-plumber developed here may serve as a clinically translatable treatment option for TBI.
Subject(s)
Brain Injuries, Traumatic , Humans , Lymphatic System/metabolism , Brain/metabolism , PrognosisABSTRACT
Mesenchymal stem cells (MSCs) exhibited remarkable therapeutic potential in ischemic stroke due to their exceptional immunomodulatory ability and paracrine effect; they have also been regarded as excellent neuroprotectant delivery vehicles with inflammatory tropism. However, the presence of high levels of reactive oxygen species (ROS) and an oxidative stress environment at the lesion site inhibits cell survival and further therapeutic effects. Using bioorthogonal click chemistry, ROS-responsive luteolin-loaded micelles were tethered to the surface of MSCs. As MSCs migrated to the ischemic brain, the micelles would achieve ROS-responsive release of luteolin to protect MSCs from excessive oxidative damage while inhibiting neuroinflammation and scavenging ROS to ameliorate ischemic stroke. This study provided an effective and prospective therapeutic strategy for ischemic stroke and a framework for a stem cell-based therapeutic system to treat inflammatory cerebral diseases.
ABSTRACT
Apoptotic vesicles (ApoVs) hold great promise for inflammatory regulation and tissue repair. However, little effort has been dedicated to developing ApoV-based drug delivery platforms, while the insufficient targeting capability of ApoVs also limits their clinical applications. This work presents a platform architecture that integrates apoptosis induction, drug loading, and functionalized proteome regulation, followed by targeting modification, enabling the creation of an apoptotic vesicle delivery system to treat ischemic stroke. Briefly, α-mangostin (α-M) was utilized to induce mesenchymal stem cell (MSC) apoptosis while being loaded onto MSC-derived ApoVs as an anti-oxidant and anti-inflammatory agent for cerebral ischemia/reperfusion injury. Matrix metalloproteinase activatable cell-penetrating peptide (MAP), a microenvironment-responsive targeting peptide, was modified on the surface of ApoVs to obtain the MAP-functionalized α-M-loaded ApoVs. Such engineered ApoVs targeted the injured ischemic brain after systemic injection and achieved an enhanced neuroprotective activity due to the synergistic effect of ApoVs and α-M. The internal protein payloads of ApoVs, upon α-M activation, were found engaged in regulating immunological response, angiogenesis, and cell proliferation, all of which contributed to the therapeutic effects of ApoVs. The findings provide a universal framework for creating ApoV-based therapeutic drug delivery systems for the amelioration of inflammatory diseases and demonstrate the potential of MSC-derived ApoVs to treat neural injury.
