Vascular disease remains the leading cause of death and disability, the etiology of which often involves atherosclerosis. The current treatment of atherosclerosis by pharmacotherapy has limited therapeutic efficacy. Here we report a biomimetic drug delivery system derived from macrophage membrane coated ROS-responsive nanoparticles (NPs). The macrophage membrane not only avoids the clearance of NPs from the reticuloendothelial system, but also leads NPs to the inflammatory tissues, where the ROS-responsiveness of NPs enables specific payload release. Moreover, the macrophage membrane sequesters proinflammatory cytokines to suppress local inflammation. The synergistic effects of pharmacotherapy and inflammatory cytokines sequestration from such a biomimetic drug delivery system lead to improved therapeutic efficacy in atherosclerosis. Comparison to macrophage internalized with ROS-responsive NPs, as a live-cell based drug delivery system for treatment of atherosclerosis, suggests that cell membrane coated drug delivery approach is likely more suitable for dealing with an inflammatory disease than the live-cell approach.
Ulcerative colitis (UC) is featured with relapsing inflammation in the colon, where macrophages are recruited and polarized locally into M1 type to drive further inflammation. Pharmacotherapy of UC has exhibited limited efficacy, mostly due to the poor specificity.
Methods:
A macrophage-biomimetic nanomedicine was developed for targeted treatment of UC, which was derived from reactive oxygen species (ROS)-sensitive β-cyclodextrin, loaded with rosiglitazone, and coated with macrophage membrane. The ability of the nanomedicine in regulating macrophage polarization was examined at cellular level, and the macrophage-tropism driven targeted delivery into the inflammatory colon was investigated by
ex vivo
bio-imaging distribution assay. Furthermore, the nanomedicine's therapeutic efficacy was systemically examined in dextran sulfate sodium (DSS)-induced colitis model in mice.
Results:
The nanomedicine effectively polarized macrophages to M2 and protected epithelial cells from oxidative stress
in vitro
. In addition, macrophage-membrane led the nanomedicine to the inflammatory colon with a high targeting efficiency. In response to the elevated ROS in the inflammatory tissue, the nanomedicine released rosiglitazone specifically and regulated macrophage polarization
in vivo
. Macrophage membrane also assisted inflammation suppression by sequestering proinflammatory cytokines. Working in such a synergy, the nanomedicine exhibited significant therapeutic effects against UC in mice.
Conclusions:
This macrophage-biomimetic nanomedicine leverages the inflammatory tropism and inflammatory cytokine sequestration effects of macrophage membrane for targeted delivery and local inflammation suppression, the ROS-responsiveness of β-cyclodextrin-based matrix for specific payload release, and the macrophage-polarizing effect of rosiglitazone for inflammatory regulation, thereby exhibiting considerable therapeutic efficacy against UC in mice. This study offers important new insights on the design and development of biomimetic nanomaterials for inflammation regulations.
Nano-graphene oxide (NGO) has attracted increasing attentions as advanced drug delivery systems. However, the current surface functionalization and drug-loading of NGO either relies on π−π stacking that is limited to...
Sonodynamic therapy (SDT) is a noninvasive technique for local antitumor treatment; however, its clinical application is often limited by the low tumor accumulation of SDT agents, tumor's hypoxic microenvironment, and cytoprotective effects of autophagy. To address these issues, herein we developed surface-engineered chlorella (Chl, a green algae) as a targeted drug carrier and sustainable oxygen supplier (via photosynthesis) for significantly improved SDT via hypoxia alleviation as well as autophagy inhibition of chloroquine phosphate. In this design, the macrophage membrane was coated onto Chl to form macrophage-mimetic Chl (MChl) to increase its biocompatibility and targeted tumor accumulation driven by the inflammatory-homing effects of macrophage membranes. In addition, the membrane coating on Chl allowed lipid insertion to yield β-cyclodextrin (β-CD) modified MChl (CD-MChl). Subsequently, supramolecular conjugates of MChl-NP were constructed via host−guest interactions between CD-MChl and adamantane (ADA)-modified liposome (ADA-NP), and the anchored liposome went with CD-MChl hand-in-hand to the tumor tissues for co-delivery of Chl, hematoporphyrin, and chloroquine phosphate (loaded in ADA-NP). The synergistic therapy achieved via local oxygenation, SDT, and autophagy inhibition maximally improved the therapeutic efficacy of MChl-CQ-HP-NP against melanoma. Tumor rechallenging results revealed that the changes of tumor microenvironment including hypoxia alleviation, SDT induced immunogenic cell death, and autophagy inhibition collectively induced a strong antitumor immune response and memory.
Cell-based drug carriers are mostly prepared in vitro, which may negatively affect the physiological functions of cells, and induce possible immune rejections when applied to different individuals. In addition, the immunosuppressive tumor microenvironment limits immune cell–mediated delivery. Here, we report an in vivo strategy to construct cell-based nanomedicine carriers, where bacteria-mimetic gold nanoparticles (GNPs) are intravenously injected, selectively phagocytosed by phagocytic immune cells, and subsequently self-assemble into sizable intracellular aggregates via host-guest interactions. The intracellular aggregates minimize exocytosis of GNPs from immune cells and activate the photothermal property via plasmonic coupling effects. Phagocytic immune cells carry the intracellular GNP aggregates to melanoma tissue via inflammatory tropism. Moreover, an initial photothermal treatment (PTT) of the tumor induces tumor damage that subsequently provides positive feedback to recruit more immune cell–based carriers for enhanced targeting efficiency. The optimized secondary PTT notably improves antitumor immunotherapy, further strengthened by immune checkpoint blockade.
In spite of the rapid emergence of numerous nanoparticles (NPs)
for biomedical applications, it is often challenging to precisely
control, or effectively tame, the bioactivity/toxicity of NPs, thereby
exhibiting limited applications in biomedical areas. Herein, we report
the construction of hyaluronic acid (HA)-laminated, otherwise toxic
methylviologen (MV), NPs via ternary host–guest
complexation among cucurbit[8]uril, trans-azobenzene-conjugated
HA, and MV-functionalized polylactic acid NPs (MV-NPs). The high,
nonspecific toxicity of MV-NPs was effectively shielded (turned off)
by HA lamination, as demonstrated in cells, zebrafish, and mouse models.
The supramolecular host–guest interaction-mediated HA coating
offered several HA-MV-NP modalities, including hyaluronidase locally
and photoirradiation remotely, to precisely remove HA lamination on
demand, thereby endowing materials with the capability of selective
decoating-induced activation (DIA) for applications as a user-friendly
herbicide, a selective antibacterial agent, or an anticancer nanomedicine.
This work offers facile supramolecular coating and DIA strategies
to effectively tame and precisely control the bioactivity and toxicity
of functional nanomaterials for diverse applications.
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