Xiaoyuan Ji

Black Phosphorus Nanosheets as a Robust Delivery Platform for Cancer Theranostics

2D black phosphorus (BP) nanomaterials are presented as a delivery platform. The endocytosis pathways and biological activities of PEGylated BP nanosheets in cancer cells are revealed for the first time. Finally, a triple-response combined therapy strategy is achieved by PEGylated BP nanosheets, showing a promising and enhanced antitumor effect.

Antimonene Quantum Dots: Synthesis and Application as Near‐Infrared Photothermal Agents for Effective Cancer Therapy

Photothermal therapy (PTT) has shown significant potential for cancer therapy. However, developing nanomaterials (NMs)-based photothermal agents (PTAs) with satisfactory photothermal conversion efficacy (PTCE) and biocompatibility remains a key challenge. Herein, a new generation of PTAs based on two-dimensional (2D) antimonene quantum dots (AMQDs) was developed by a novel liquid exfoliation method. Surface modification of AMQDs with polyethylene glycol (PEG) significantly enhanced both biocompatibility and stability in physiological medium. The PEG-coated AMQDs showed a PTCE of 45.5 %, which is higher than many other NMs-based PTAs such as graphene, Au, MoS2 , and black phosphorus (BP). The AMQDs-based PTAs also exhibited a unique feature of NIR-induced rapid degradability. Through both in vitro and in vivo studies, the PEG-coated AMQDs demonstrated notable NIR-induced tumor ablation ability. This work is expected to expand the utility of 2D antimonene (AM) to biomedical applications through the development of an entirely novel PTA platform.

ROS-Responsive Polyprodrug Nanoparticles for Triggered Drug Delivery and Effective Cancer Therapy

The application of nanoparticles (NPs) to drug delivery has led to the development of novel nanotherapeutics for the treatment of various diseases including cancer. However, clinical use of NP-mediated drug delivery has not always translated into improved survival of cancer patients, in part due to the suboptimal properties of NP platforms, such as premature drug leakage during preparation, storage, or blood circulation, lack of active targeting to tumor tissue and cells, and poor tissue penetration. Herein, an innovative reactive oxygen species (ROS)-responsive polyprodrug is reported that can self-assemble into stable NPs with high drug loading. This new NP platform is composed of the following key components: (i) polyprodrug inner core that can respond to ROS for triggered release of intact therapeutic molecules, (ii) polyethylene glycol (PEG) outer shell to prolong blood circulation; and (iii) surface-encoded internalizing RGD (iRGD) to enhance tumor targeting and tissue penetration. These targeted ROS-responsive polyprodrug NPs show significant inhibition of tumor cell growth both in vitro and in vivo.

Comprehensive Insights into the Multi-Antioxidative Mechanisms of Melanin Nanoparticles and Their Application To Protect Brain from Injury in Ischemic Stroke

Nanotechnology-mediated antioxidative therapy is emerging as a novel strategy for treating a myriad of important diseases through scavenging excessive reactive oxygen and nitrogen species (RONS), a mechanism critical in disease development and progression. However, similar to antioxidative enzymes, currently studied nanoantioxidants have demonstrated scavenging activity to specific RONS, and sufficient antioxidative effects against multiple RONS generated in diseases remain elusive. Here we propose to develop bioinspired melanin nanoparticles (MeNPs) for more potent and safer antioxidative therapy. While melanin is known to function as a potential radical scavenger, its antioxidative mechanisms are far from clear, and its applications for the treatment of RONS-associated diseases have yet to be well-explored. In this study, we provide for the first time exhaustive characterization of the activities of MeNPs against multiple RONS including O2•-, H2O2, •OH, •NO, and ONOO-, the main toxic RONS generated in diseases. The potential of MeNPs for antioxidative therapy has also been evaluated in vitro and in a rat model of ischemic stroke. In addition to the broad defense against these RONS, MeNPs can also attenuate the RONS-triggered inflammatory responses through suppressing the expression of inflammatory mediators and cytokines. In vivo results further demonstrate that these unique multi-antioxidative, anti-inflammatory, and biocompatible features of MeNPs contribute to their effective protection of ischemic brains with negligible side effects.

Tumor Microenvironment-Responsive Multistaged Nanoplatform for Systemic RNAi and Cancer Therapy

While RNA interference (RNAi) therapy has demonstrated significant potential for cancer treatment, the effective and safe systemic delivery of RNAi agents such as small interfering RNA (siRNA) into tumor cells in vivo remains challenging. We herein reported a unique multistaged siRNA delivery nanoparticle (NP) platform, which is comprised of (i) a polyethylene glycol (PEG) surface shell, (ii) a sharp tumor microenvironment (TME) pH-responsive polymer that forms the NP core, and (iii) charge-mediated complexes of siRNA and tumor cell-targeting- and penetrating-peptide-amphiphile (TCPA) that are encapsulated in the NP core. When the rationally designed, long circulating polymeric NPs accumulate in tumor tissues after intravenous administration, the targeted siRNA-TCPA complexes can be rapidly released via TME pH-mediated NP disassembly for subsequent specific targeting of tumor cells and cytosolic transport, thus achieving efficient gene silencing. In vivo results further demonstrate that the multistaged NP delivery of siRNA against bromodomain 4 (BRD4), a recently discovered target protein that regulates the development and progression of prostate cancer (PCa), can significantly inhibit PCa tumor growth.

Intracellular Mechanistic Understanding of 2D MoS2 Nanosheets for Anti-Exocytosis-Enhanced Synergistic Cancer Therapy

Emerging two-dimensional (2D) nanomaterials, such as transition-metal dichalcogenide (TMD) nanosheets (NSs), have shown tremendous potential for use in a wide variety of fields including cancer nanomedicine. The interaction of nanomaterials with biosystems is of critical importance for their safe and efficient application. However, a cellular-level understanding of the nano-bio interactions of these emerging 2D nanomaterials ( i. e., intracellular mechanisms) remains elusive. Here we chose molybdenum disulfide (MoS2) NSs as representative 2D nanomaterials to gain a better understanding of their intracellular mechanisms of action in cancer cells, which play a significant role in both their fate and efficacy. MoS2 NSs were found to be internalized through three pathways: clathrin → early endosomes → lysosomes, caveolae → early endosomes → lysosomes, and macropinocytosis → late endosomes → lysosomes. We also observed autophagy-mediated accumulation in the lysosomes and exocytosis-induced efflux of MoS2 NSs. Based on these findings, we developed a strategy to achieve effective and synergistic in vivo cancer therapy with MoS2 NSs loaded with low doses of drug through inhibiting exocytosis pathway-induced loss. To the best of our knowledge, this is the first systematic experimental report on the nano-bio interaction of 2D nanomaterials in cells and their application for anti-exocytosis-enhanced synergistic cancer therapy.

Tantalum Sulfide Nanosheets as a Theranostic Nanoplatform for Computed Tomography Imaging-Guided Combinatorial Chemo-Photothermal Therapy

Near-infrared (NIR)-absorbing metal-based nanomaterials have shown tremendous potential for cancer therapy, given their facile and controllable synthesis, efficient photothermal conversion, capability of spatiotemporal-controlled drug delivery, and intrinsic imaging function. Tantalum (Ta) is among the most biocompatible metals and arouses negligible adverse biological responses in either oxidized or reduced forms, and thus Ta-derived nanomaterials represent promising candidates for biomedical applications. However, Ta-based nanomaterials by themselves have not been explored for NIR-mediated photothermal ablation therapy. In this work, we report an innovative Ta-based multifunctional nanoplatform composed of biocompatible tantalum sulfide (TaS2) nanosheets (NSs) for simultaneous NIR hyperthermia, drug delivery, and computed tomography (CT) imaging. The TaS2 NSs exhibit multiple unique features including (i) efficient NIR light-to-heat conversion with a high photothermal conversion efficiency of 39%. (ii) high drug loading (177% by weight), (iii) controlled drug release triggered by NIR light and moderate acidic pH, (iv) high tumor accumulation via heat-enhanced tumor vascular permeability, (v) complete tumor ablation and negligible side effects, and (vi) comparable CT imaging contrast efficiency to the widely clinically used agent iobitridol. We expect that this multifunctional NS platform can serve as a promising candidate for imaging-guided cancer therapy and selection of cancer patients with high tumor accumulation.

Surface De-PEGylation Controls Nanoparticle-Mediated siRNA Delivery In Vitro and In Vivo

The present work proposes a unique de-PEGylation strategy for controllable delivery of small interfering RNA (siRNA) using a robust lipid-polymer hybrid nanoparticle (NP) platform. The self-assembled hybrid NPs are composed of a lipid-poly(ethylene glycol) (lipid-PEG) shell and a polymer/cationic lipid solid core, wherein the lipid-PEG molecules can gradually dissociate from NP surface in the presence of serum albumin. The de-PEGylation kinetics of a series of different lipid-PEGs is measured with their respective NPs, and the NP performance is comprehensively investigated in vitro and in vivo. This systematic study reveals that the lipophilic tails of lipid-PEG dictate its dissociation rate from NP surface, determining the uptake by tumor cells and macrophages, pharmacokinetics, biodistribution, and gene silencing efficacy of these hybrid siRNA NPs. Based on our observations, we here propose that lipid-PEGs with long and saturated lipophilic tails might be required for effective siRNA delivery to tumor cells and gene silencing of the lipid-polymer hybrid NPs after systemic administration.

Engineering Multifunctional RNAi Nanomedicine To Concurrently Target Cancer Hallmarks for Combinatorial Therapy

Cancer hallmarks allow the complexity and heterogeneity of tumor biology to be better understood, leading to the discovery of various promising targets for cancer therapy. An amorphous iron oxide nanoparticle (NP)-based RNAi strategy is developed to co-target two cancer hallmarks. The NP technology can modulate the glycolysis pathway by silencing MCT4 to induce tumor cell acidosis, and concurrently exacerbate oxidative stress in tumor cells via the Fenton-like reaction. This strategy has the following features for systemic siRNA delivery: 1) siRNA encapsulation within NPs for improving systemic stability; 2) effective endosomal escape through osmotic pressure and/or endosomal membrane oxidation; 3) small size for enhancing tumor tissue penetration; and 4) triple functions (RNAi, Fenton-like reaction, and MRI) for combinatorial therapy and in vivo tracking.

Two‐Dimensional Antimonene‐Based Photonic Nanomedicine for Cancer Theranostics

Antimonene (AM) is a recently described two-dimensional (2D) elemental layered material. In this study, a novel photonic drug-delivery platform based on 2D PEGylated AM nanosheets (NSs) is developed. The platforms multiple advantages include: i) excellent photothermal properties, ii) high drug-loading capacity, iii) spatiotemporally controlled drug release triggered by near-infrared (NIR) light and moderate acidic pH, iv) superior accumulation at tumor sites, v) deep tumor penetration by both extrinsic stimuli (i.e., NIR light) and intrinsic stimuli (i.e., pH), vi) excellent multimodal-imaging properties, and vii) significant inhibition of tumor growth with no observable side effects and potential degradability, thus addressing several key limitations of cancer nanomedicines. The intracellular fate of the prepared NSs is also revealed for the first time, providing deep insights that improve cellular-level understanding of the nano-bio interactions of AM-based NSs and other emerging 2D nanomaterials. To the best of knowledge, this is the first report on 2D AM-based photonic drug-delivery platforms, possibly marking an exciting jumping-off point for research into the application of 2D AM nanomaterials in cancer theranostics.