Xiao Fu

NIR‐Responsive On‐Demand Release of CO from Metal Carbonyl‐Caged Graphene Oxide Nanomedicine

On-demand release of carbon monoxide (CO) is realized through a novel near-infrared-responsive nanomedicine in favor of the enhancement of therapy efficacy and biosafety of CO therapy.

Transformative Nanomedicine of an Amphiphilic Camptothecin Prodrug for Long Circulation and High Tumor Uptake in Cancer Therapy

We report a camptothecin (CPT) prodrug that was well formulated in solution and rapidly transformed into long-circulating nanocomplexes in vivo for highly efficient drug delivery and effective cancer therapy. Specifically, using a redox-responsive disulfide linker, CPT was conjugated with an albumin-binding Evans blue (EB) derivative; the resulting amphiphilic CPT-ss-EB prodrug self-assembled into nanostructures in aqueous solution, thus conferring high solubility and stability. By binding CPT-ss-EB to endogenous albumin, the 80 nm CPT-ss-EB nanoparticles rapidly transformed into 7 nm albumin/prodrug nanocomplexes. CPT-ss-EB was efficient at intracellular delivery into cancer cells, released intact CPT in a redox-responsive manner, and exhibited cytotoxicity as potent as CPT. In mice, the albumin/CPT-ss-EB nanocomplex exhibited remarkably long blood circulation (130-fold greater than CPT) and efficient tumor accumulation (30-fold of CPT), which consequently contributed to excellent therapeutic efficacy. Overall, this strategy of transformative nanomedicine is promising for efficient drug delivery.

Core–Satellite Polydopamine–Gadolinium-Metallofullerene Nanotheranostics for Multimodal Imaging Guided Combination Cancer Therapy

Integration of magnetic resonance imaging (MRI) and other imaging modalities is promising to furnish complementary information for accurate cancer diagnosis and imaging-guided therapy. However, most gadolinium (Gd)-chelator MR contrast agents are limited by their relatively low relaxivity and high risk of released-Gd-ions-associated toxicity. Herein, a radionuclide-64 Cu-labeled doxorubicin-loaded polydopamine (PDA)-gadolinium-metallofullerene core-satellite nanotheranostic agent (denoted as CDPGM) is developed for MR/photoacoustic (PA)/positron emission tomography (PET) multimodal imaging-guided combination cancer therapy. In this system, the near-infrared (NIR)-absorbing PDA acts as a platform for the assembly of different moieties; Gd3 N@C80 , a kind of gadolinium metallofullerene with three Gd ions in one carbon cage, acts as a satellite anchoring on the surface of PDA. The as-prepared CDPGM NPs show good biocompatibility, strong NIR absorption, high relaxivity (r 1 = 14.06 mM-1 s-1 ), low risk of release of Gd ions, and NIR-triggered drug release. In vivo MR/PA/PET multimodal imaging confirms effective tumor accumulation of the CDPGM NPs. Moreover, upon NIR laser irradiation, the tumor is completely eliminated with combined chemo-photothermal therapy. These results suggest that the CDPGM NPs hold great promise for cancer theranostics.

Polyrotaxane-based supramolecular theranostics

The development of smart theranostic systems with favourable biocompatibility, high loading efficiency, excellent circulation stability, potent anti-tumour activity, and multimodal diagnostic functionalities is of importance for future clinical application. The premature burst release and poor degradation kinetics indicative of polymer-based nanomedicines remain the major obstacles for clinical translation. Herein we prepare theranostic shell-crosslinked nanoparticles (SCNPs) using a β-cyclodextrin-based polyrotaxane (PDI-PCL-b-PEG-RGD⊃β-CD-NH2) to avoid premature drug leakage and achieve precisely controllable release, enhancing the maximum tolerated dose of the supramolecular nanomedicines. cRGDfK and perylene diimide are chosen as the stoppers of PDI-PCL-b-PEG-RGD⊃β-CD-NH2, endowing the resultant SCNPs with excellent integrin targeting ability, photothermal effect, and photoacoustic capability. In vivo anti-tumour studies demonstrate that drug-loaded SCNPs completely eliminate the subcutaneous tumours without recurrence after a single-dose injection combining chemotherapy and photothermal therapy. These supramolecular nanomedicines also exhibit excellent anti-tumour performance against orthotopic breast cancer and prevent lung metastasis with negligible systemic toxicity.Multifunctional nanomedicine platforms are highly promising for anticancer therapy. Here, the authors design polyrotaxane-based theranostic nanoparticles that combine targeted drug delivery with photothermal behaviour to exhibit potent anti-tumour effects in vivo.

Albumin/vaccine nanocomplexes that assemble in vivo for combination cancer immunotherapy

Subunit vaccines have been investigated in over 1000 clinical trials of cancer immunotherapy, but have shown limited efficacy. Nanovaccines may improve efficacy but have rarely been clinically translated. By conjugating molecular vaccines with Evans blue (EB) into albumin-binding vaccines (AlbiVax), here we develop clinically promising albumin/AlbiVax nanocomplexes that self-assemble in vivo from AlbiVax and endogenous albumin for efficient vaccine delivery and potent cancer immunotherapy. PET pharmacoimaging, super-resolution microscopies, and flow cytometry reveal almost 100-fold more efficient co-delivery of CpG and antigens (Ags) to lymph nodes (LNs) by albumin/AlbiVax than benchmark incomplete Freund’s adjuvant (IFA). Albumin/AlbiVax elicits ~10 times more frequent peripheral antigen-specific CD8+ cytotoxic T lymphocytes with immune memory than IFA-emulsifying vaccines. Albumin/AlbiVax specifically inhibits progression of established primary or metastatic EG7.OVA, B16F10, and MC38 tumors; combination with anti-PD-1 and/or Abraxane further potentiates immunotherapy and eradicates most MC38 tumors. Albumin/AlbiVax nanocomplexes are thus a robust platform for combination cancer immunotherapy.Albumin conjugates can enhance drug delivery. Here, the authors repurpose albumin-binding Evans blue to develop nanovaccines that co-deliver adjuvants and tumor neoantigens to antigen-presenting cells in lymph nodes, resulting in potent and durable antitumour immunity in combination immunotherapy.

Polymeric Nanovehicle Regulated Spatiotemporal Real-Time Imaging of the Differentiation Dynamics of Transplanted Neural Stem Cells after Traumatic Brain Injury

Recent advances in neural stem cell (NSC) transplantation have led to an inspiring progress in alleviating central nervous system (CNS) damages and restoring brain functions from diseases or injuries. One challenge of NSC transplantation is directed differentiation of transplanted NSCs into desired neuronal subtypes, such as neurons, to compensate the adverse impact of brain injury; another challenge lies in the lack of tools to noninvasively monitor the dynamics of NSC differentiation after transplantation in vivo. In this study, we developed a polymer nanovehicle for morphogen sustained release to overcome the drawbacks of conventional methods to realize the long-term directed NSC differentiation in vivo. Moreover, we constructed a bicistronic vector with a unique neuron specific gene tubb3 promoter to drive reporter gene expression for real-time imaging of NSC differentiation and migration. The developed uniform nanovehicle showed efficient NSC uptake and achieved a controlled release of morphogen in cytosol to consistently stimulate NSC differentiation into neurons at a sustainably effective concentration. The spatiotemporal imaging results showed a multiplexed migration, proliferation, differentiation, and apoptosis orchestra of transplanted NSCs regulated by nanovehicles in TBI mice. The imaging results also uncovered the peak time of NSC differentiation in vivo. Although we observed only a handful of NSCs ultimately migrated to the TBI area and differentiated into neurons, those neurons were functional, ameliorating the detrimental impact of TBI. The imaging findings enabled by the nanovehicle and the neuron specific bicistronic vector provide additional understanding of the in vivo behaviors of transplanted NSCs in neuronal regenerative medicine.

Suppressing Nanoparticle-Mononuclear Phagocyte System Interactions of Two-Dimensional Gold Nanorings for Improved Tumor Accumulation and Photothermal Ablation of Tumors

The clearance of nanoparticles (NPs) by mononuclear phagocyte system (MPS) from blood leads to high liver and spleen uptake and negatively impacts their tumor delivery efficiency. Here we systematically evaluated the in vitro and in vivo nanobio interactions of a two-dimensional (2D) model, gold (Au) nanorings, which were compared with Au nanospheres and Au nanoplates of similar size. Among different shapes, Au nanorings achieved the lowest MPS uptake and highest tumor accumulation. Among different sizes, 50 nm Au nanorings showed the highest tumor delivery efficiency. In addition, we demonstrated the potential use of Au naonrings in photoacoustic imaging and photothermal therapy. Thus, engineering the shape, surface area, and size of Au nanostructures is important in controlling NP-MPS interactions and improving the tumor uptake efficiency.

A supramolecular hybrid material constructed from graphene oxide and a pillar[6]arene-based host–guest complex as an ultrasound and photoacoustic signal nanoamplifier

Photoacoustic imaging combines the merits of ultrasound imaging and optical imaging that allows a fascinating imaging paradigm with deeper tissue penetration than optical imaging and higher spatial resolution than ultrasound imaging. Herein, we develop a supramolecular hybrid material composed of graphene oxide (GO) and a pillar[6]arene-based host-guest complex (CP6⊃PyN), which can be used as a ultrasound (US) and photoacoustic (PA) signal nanoamplifier. Triggered by the near-infrared (NIR) light mediated photothermal effect, CO2 nanobubbles are generated on the surface of GO@CP6⊃PyN due to the decomposition of bicarbonate counterions, thus strongly amplifying its US and PA performances. Our study, for the first time, demonstrates enhanced US and PA activity in supramolecular hybrid material on the basis of host-guest chemistry as a photoacoustic nanoplatform.

Black Phosphorus Nanosheets for Mild Hyperthermia-Enhanced Chemotherapy and Chemo-Photothermal Combination Therapy

Near-infrared (NIR) light triggered photothermally enhanced cellular internalization strategy shows great potential to improve antitumor effect to fight against cancer. In this work, a black phosphorus (BP) nanosheet-based nanomedicine, which is composed of BP nanosheet, human serum albumin (HSA) and paclitaxel (PTX), was developed for mild hyperthermia-enhanced intracellular drug delivery and chemo-photothermal combination therapy. BP nanosheet was successfully synthesized by a one-pot biomimetic synthesis method using HSA as exfoliating agent and capping agent. Meanwhile, PTX can be efficiently loaded by HSA via hydrophobic interactions. The PTX-loaded HSA functionalized BP (BP-HSA-PTX) exhibits great photothermal performance, excellent biodegradability/biocompatibility, and effective drug loading. Upon NIR laser illumination, mild hyperthermia (~43 °C) or photothermal effect can be achieved to improve the intracellular drug delivery efficiency and antitumor effect of BP-HSA-PTX. Our results indicate that HSA-functionalized BP has great potential for the loading, delivery, cellular uptake enhancement of chemotherapeutics and chemo-photothermal combination antitumor effect.

Intertwining DNA-RNA nanocapsules loaded with tumor neoantigens as synergistic nanovaccines for cancer immunotherapy

Nanomedicines that co-deliver DNA, RNA, and peptide therapeutics are highly desirable yet remain underdeveloped for cancer theranostics. Herein, we report self-assembled intertwining DNA-RNA nanocapsules (iDR-NCs) that efficiently delivered synergistic DNA CpG and short hairpin RNA (shRNA) adjuvants, as well as tumor-specific peptide neoantigens into antigen presenting cells (APCs) in lymph nodes for cancer immunotherapy. These nanovaccines were prepared by (1) producing tandem CpG and shRNA via concurrent rolling circle replication and rolling circle transcription, (2) self-assembling CpG and shRNA into DNA-RNA microflowers, (3) shrinking microflowers into iDR-NCs using PEG-grafted cationic polypeptides, and (4) physically loading neoantigen into iDR-NCs. CpG and shRNA in iDR-NCs synergistically activate APCs for sustained antigen presentation. Remarkably, iDR-NC/neoantigen nanovaccines elicit 8-fold more frequent neoantigen-specific peripheral CD8+ T cells than CpG, induce T cell memory, and significantly inhibit the progression of neoantigen-specific colorectal tumors. Collectively, iDR-NCs represent potential DNA/RNA/peptide triple-co-delivery nanocarriers and synergistic tumor immunotherapeutic nanovaccines.Nucleic acid nanomedicines are promising for cancer drug delivery. Here, the authors show using a mouse model the tumor immunotherapeutic efficacy of nanovaccines based on intertwining DNA-RNA nanocapsules loaded with DNA CpG, Stat3-silencing short hairpin RNA and tumor-specific peptide neoantigens.