A Virus‐Mimicking pH‐Responsive Acetalated Dextran‐Based Membrane‐Active Polymeric Nanoparticle for Intracellular Delivery of Antitumor Therapeutics

Achieving cellular internalization and endosomal escape remains a major challenge for many antitumor therapeutics, especially macromolecular drugs. Viral drug carriers are reported for efficient intracellular delivery, but with limited choices of payloads. In this study, a novel polymeric nanoparticle (ADMAP) is developed, resembling the structure and functional features of a virus. ADMAP is synthesized by grafting endosomolytic poly(lauryl methacrylate‐co‐methacrylic acid) on acetalated dextran. The endosomolytic polymer mimics the capsid protein for endosomal escape, and acetalated dextran resembles the viral core for accommodating payloads. After polymer synthesis, the subsequent controlled nanoprecipitation on a microfluidic device yields uniform nanoparticles with high encapsulation efficiency. At late endosomal pH (5.0), the ADMAP particles successfully destabilize endosomal membranes and release the drug payloads synergistically, resulting in a greater therapeutic efficacy compared with that of free anticancer drugs. Further conjugation of a tumor‐penetrating peptide enhances the antitumor efficacy toward 3D spheroids and finally leads to spheroid disintegration. The unique structure along with the synergistic endosomal escape and drug release make ADMAP nanoparticles favorable for intracellular delivery of antitumor therapeutics.     

Off‐Stoichiometric Thiol‐Ene Chemistry to Dendritic Nanogel Therapeutics

A novel platform of dendritic nanogels is herein presented, capitalizing on the self‐assembly of allyl‐functional polyesters based on dendritic‐linear‐dendritic amphiphiles followed by simple cross‐linking with complementary monomeric thiols via UV initiated off‐stoichiometric thiol‐ene chemistry. The facile approach enabled multigram creation of allyl reactive nanogel precursors, in the size range of 190–295 nm, being readily available for further modifications to display a number of core functionalities while maintaining the size distribution and characteristics of the master batch. The nanogels are evaluated as carriers of a spread of chemotherapeutics by customizing the core to accommodate each individual cargo. The resulting nanogels are biocompatible, displaying diffusion controlled release of cargo, maintained therapeutic efficacy, and decreased cargo toxic side effects. Finally, the nanogels are found to successfully deliver pharmaceuticals into a 3D pancreatic spheroids tumor model.     

Antitumor Platelet‐Mimicking Magnetic Nanoparticles

Nanoparticles possess the potential to revolutionize cancer diagnosis and therapy. The ideal theranostic nanoplatform should own long system circulation and active cancer targeting. Additionally, it should be nontoxic and invisible to the immune system. Here, the authors fabricate an all‐in‐one nanoplatform possessed with these properties for personalized cancer theranostics. Platelet‐derived vesicles (PLT‐vesicles) along with their membrane proteins are collected from mice blood and then coated onto Fe₃O₄ magnetic nanoparticles (MNs). The resulting core–shell PLT‐MNs, which inherit the long circulation and cancer targeting capabilities from the PLT membrane shell and the magnetic and optical absorption properties from the MN core, are finally injected back into the donor mice for enhanced tumor magnetic resonance imaging (MRI) and photothermal therapy (PTT). Meanwhile, it is found that the PTT treatment impels PLT‐MNs targeting to the PTT sites (i.e., tumor sites), and exactly, in turn, the enhanced targeting of PLT‐MNs to tumor sites can improve the PTT effects. In addition, since the PLT membrane coating is obtained from the mice and finally injected into the same mice, PLT‐MNs exhibit stellar immune compatibility. The work presented here provides a new angle on the design of biomimetic nanoparticles for personalized diagnosis and therapy of various diseases.     

Remote‐Loaded Platelet Vesicles for Disease‐Targeted Delivery of Therapeutics

The recent emergence of biomimetic nanotechnology has facilitated the development of next‐generation nanodelivery systems capable of enhanced biointerfacing. In particular, the direct use of natural cell membranes can enable multivalent targeting functionalities. Herein, this study reports on the remote loading of small molecule therapeutics into cholesterol‐enriched platelet membrane‐derived vesicles for disease‐targeted delivery. Using this approach, high loading yields for two model drugs, doxorubicin and vancomycin, are achieved. Leveraging the surface markers found on platelet membranes, the resultant nanoformulations demonstrate natural affinity toward both breast cancer cells and methicillin‐resistant Staphylococcus aureus. In vivo, this translates to improved disease targeting, increasing the potency of the encapsulated drug payloads compared with free drugs and the corresponding nontargeted nanoformulations. Overall, this work demonstrates that the remote loading of drugs into functional platelet membrane‐derived vesicles is a facile means of fabricating targeted nanoformulations, an approach that can be easily generalized to other cell types in the future.     

Dual Acid‐Responsive Micelle‐Forming Anticancer Polymers as New Anticancer Therapeutics

Cinnamaldehyde, a major active compound of cinnamon, is known to induce apoptotic cell death in numerous human cancer cells. Here, dual acid‐responsive polymeric micelle‐forming cinnamaldehyde prodrugs, poly[(3‐phenylprop‐2‐ene‐1,1‐diyl)bis(oxy)bis(ethane‐2,1‐diyl)diacrylate]‐co‐4,4’(trimethylene dipiperidine)‐co‐poly(ethylene glycol), termed PCAE copolymers, are reported. PCAE is designed to incorporate cinnamaldehyde via acid‐cleavable acetal linkages in its pH‐sensitive hydrophobic backbone and self assemble to form stable micelles which can encapsulate camptothecin (CPT). PCAE self assembles to form micelles which release CPT and cinnamaldehyde in pH‐dependent manners. PCAE micelles induce apoptotic cell death through the generation of intracellular reactive oxygen species (ROS) and exert synergistic anticancer effects with a payload of CPT in vitro and in vivo model of SW620 human colon tumor‐bearing mice. It is anticipated that dual acid‐sensitive micelle‐forming PCAE with intrinsic anticancer activities has enormous potential as novel anticancer therapeutics.     

On‐Chip Fabrication of Paclitaxel‐Loaded Chitosan Nanoparticles for Cancer Therapeutics

The use of solvent‐free microfluidics to fine‐tune the physical and chemical properties of chitosan nanoparticles for drug delivery is demonstrated. Nanoparticle self‐assembly is driven by pH changes in a water environment, which increases biocompatibility by avoiding organic solvent contamination common with traditional techniques. Controlling the time of mixing (2.5–75 ms) during nanoparticle self‐assembly enables us to adjust nanoparticle size and surface potential in order to maximize cellular uptake, which in turn dramatically increases drug effectiveness. The compact nanostructure of these nanoparticles preserves drug potency better than previous nanoparticles, and is more stable during long‐term circulation at physiological pH. However, when the nanoparticles encounter a tumor cell and the associated drop in pH, the drug contents are released. Moreover, the loading efficiency of hydrophobic drugs into the nanoparticles increases significantly from previous work to over 95%. The microfluidic techniques used here have applications not just for drug‐carrying nanoparticle fabrication, but also for the better control of virtually any self‐assembly process.     

A Drug‐Self‐Gated Mesoporous Antitumor Nanoplatform Based on pH‐Sensitive Dynamic Covalent Bond

To achieve on‐demand drug release, mesoporous silica nanocarriers as antitumor platforms generally need to be gated with stimuli‐responsive capping agents. Herein, a “smart” mesoporous nanocarrier that is gated by the drug itself through a pH‐sensitive dynamic benzoic–imine covalent bond is demonstrated. The new system, which tactfully bypasses the use of auxiliary capping agents, could also exhibit desirable drug release at tumor tissues/cells and enhanced tumor inhibition. Moreover, a facile dynamic PEGylation via benzoic–imine bond further endows the drug‐self‐gated nanocarrier with tumor extracellular pH‐triggered cell uptake and improves therapeutic efficiency in vivo. In short, the paradigm shift in capping agents here will simplify mesoporous nanomaterials as intelligent drug carriers for cancer therapy. Moreover, the self‐gated strategy in this work also shows general potential for self‐controlled delivery of natural biomolecules, for example, DNA/RNA, peptides, and proteins, due to their intrinsic amino groups.     

Targeted Single‐Cell Therapeutics with Magnetic Tubular Micromotor by One‐Step Exposure of Structured Femtosecond Optical Vortices

Selective manipulation of specific single cells for therapeutics is important and highly desirable in biomedical research. As a simple and maneuverable tool, tubular micromotors have displayed appealing applications in encapsulation and transportation of cells. However, so far there are no reports on the simultaneous transportation of target single cells and the drugs with microtubes in a custom arrayed environment for targeted therapeutics. Moreover, fabrication of microtubes with 3D features in a reproducible and single‐step fashion, while, endowing them with the ability of remote control, remains challenging. In this study, a novel method for one‐step fabrication of magnetic 3D tubular micromotors by single exposure of structured optical vortices in a magnetic photoresist is presented. The size and geometry of fabricated microtubes are flexibly controlled in three dimensions. Precise propelling of the tubular micromotors and precise capture, targeted delivery, and release of SiO₂ microparticles are realized. Finally, as a proof‐of‐concept demonstration, in situ observation of the development of doxorubicin in Hela cells for therapeutic study is performed by targeted delivery of single cells and drug particles. The technology is simple and stable, which has promising applications in targeted cell therapy, drug screening, single cell studies, and other biomedical areas.     

Safe‐by‐Design Exfoliation of Niobium Diselenide Atomic Crystals as a Theory‐Oriented 2D Nanoagent from Anti‐Inflammation to Antitumor

The accompanying relationship between tumor and inflammation raises the concept of concurrent antitumor and anti‐inflammation treatment in the clinic. Despite the wide application of 2D atomic crystals for cancer theranostics, their anti‐inflammation function has been rarely explored. Herein, it is reported that niobium diselenide nanosheets (NbSe₂ NSs), a “star” 2D superconducting atomic crystal, can serve as a theory‐oriented 2D nanoagent from anti‐inflammation to antitumor. A safe‐by‐design exfoliation strategy, integration of cryo‐pretreatment and DNA‐assisted exfoliation, is proposed for high‐efficiency exfoliation of atomically thin NbSe₂ NSs. Especially, computational simulation reveals that NbSe₂ NSs effectively eliminate reactive oxygen and nitrogen species (RONS) via hydrogen atom transfer and redox reaction. Upon the injection of NbSe₂ NSs into BALB/c mice, not only U87 subcutaneous tumors are rapidly ablated after photoacoustic imaging‐guided precise localization of tumor contour, but also lipopolysaccharide‐induced rear thigh inflammation or photothermal therapy‐mediated inflammation is efficiently inhibited through RONS scavenging. In addition, NbSe₂ NSs are highly biocompatible both in vitro and in vivo due to high‐security element constituent and DNA modification. The work extends the biomedical application of 2D atomic crystals for anti‐inflammatory treatment.     

From Nanofibers to Nanorods: Nanostructure of Peptide‐Drug Conjugates Regulated by Polypeptide‐PEG Derivative and Enhanced Antitumor Effect

Peptide‐drug conjugates (PDCs) are a type of self‐assembled prodrug with good potential for drug delivery due to their excellent biocompatibility, high drug loading, and permanent controllable release. However, most PDCs tend to self‐assemble into filamentous nanostructures in water and under physiological conditions, making them unsuitable as intravenous formulations due to the entanglement of long fibers and the risk of thrombus. Injected PDCs also face challenges in overcoming the complex physiological environment to reach the target site. To expand their clinical use, it is necessary to control the properties of PDC, including the self‐assembled structure and physiological performance, to avoid the above problems. Based on assembly mechanism studies of PDCs, a new method for regulating PDC morphology is developed by controlling intermolecular interactions in the assembly process. This method can alter the final morphology of PDCs from nanofibers to nanorods, and the introduced macromolecules endow the PDC with new characteristics that facilitate stable and high‐efficiency access to the target site.     

Enhanced Antitumor Efficacy by 808 nm Laser‐Induced Synergistic Photothermal and Photodynamic Therapy Based on a Indocyanine‐Green‐Attached W18O49 Nanostructure

A novel nanoplatform based on tungsten oxide (W₁₈O₄₉, WO) and indocyanine green (ICG) for dual‐modal photothermal therapy (PTT) and photodynamic therapy (PDT) has been successfully constructed. In this design, the hierarchical unique nanorod‐bundled W₁₈O₄₉ nanostructures play roles in being not only as an efficient photothermal agent for PTT but also as a potential nanovehicle for ICG molecules via electrostatic adsorption after modified with trimethylammonium groups on their surface. It is found that the ability of ICG to produce cytotoxic reactive oxygen species for PDT is well maintained after being attached on the WO, thus the as‐obtained WO@ICG can achieve a synergistic effect of combined PTT and PDT under single 808 nm near‐infrared (NIR) laser excitation. Notably, compared with PTT or PDT alone, the enhanced HeLa cells lethality of the 808 nm laser triggered dual‐modal therapy is observed. The in vivo animal experiments have shown that WO@ICG has effective solid tumor ablation effect with 808 nm NIR light irradiation, revealing the potential of these nanocomposites as a NIR‐mediated dual‐modal therapeutic platform for cancer treatment.     

Exosome as a Vehicle for Delivery of Membrane Protein Therapeutics,PH20, for Enhanced Tumor Penetration and Antitumor Efficacy

As biochemical and functional studies of membrane protein remain a challenge, there is growing interest in the application of nanotechnology to solve the difficulties of developing membrane protein therapeutics. Exosome, composed of lipid bilayer enclosed nanosized extracellular vesicles, is a successful platform for providing a native membrane composition. This study reports an enzymatic exosome, which harbors native PH20 hyaluronidase (Exo‐PH20), which is able to penetrate deeply into tumor foci via hyaluronan degradation, allowing tumor growth inhibition and increased T cell infiltration into the tumor. This exosome‐based strategy is developed to overcome the immunosuppressive and anticancer therapy‐resistant tumor microenvironment, which is characterized by an overly accumulated extracellular matrix. Notably, this engineered exosome with the native glycosylphosphatidylinositol‐anchored form of hyaluronidase has a higher enzymatic activity than a truncated form of the recombinant protein. In addition, the exosome‐mediated codelivery of PH20 hyaluronidase and a chemotherapeutic (doxorubicin) efficiently inhibits tumor growth. This exosome is designed to degrade hyaluronan, thereby augmenting nanoparticle penetration and drug diffusion. The results thus show that this is a promising exosome‐based platform that harbors not only a membrane‐associated enzyme with high activity but also therapeutic payloads.     

The Antitumor Efficacy of CpG Oligonucleotides is Improved by Encapsulation in Plant Virus‐Like Particles

Oligodeoxynucleotides (ODNs) with CpG motifs have potent immunostimulatory effects on many subsets of immune cells. For example, Class B CpG‐ODNs, such as ODN1826 induce the phagocytic activity of macrophages by activating the Toll‐like receptor 9 signaling pathway. Systemic ODN delivery results in unfavorable pharmacokinetic profiles and can trigger adverse effects. To address this issue, plant virus‐like particles (VLPs) are developed for the targeted delivery of ODN1826 to tumor‐associated macrophages (TAMs). ODN1826 is encapsulated by the in vitro disassembly and reassembly of Cowpea chlorotic mottle virus (CCMV), producing VLPs that are structurally analogous to the native virus. The encapsulation of ODN1826 in CCMV‐derived VLPs promotes ODN uptake by TAMs ex vivo and significantly enhance their phagocytic activity. The antitumor activity of the VLPs in vivo is also evaluated, revealing that the direct injection of ODN1826 VLPs into established tumors induces a robust antitumor response by increasing the phagocytic activity of TAMs in the tumor microenvironment. CCMV encapsulation significantly enhances the efficacy of ODN1826 compared to the free drug, slowing tumor growth and prolonging survival in mouse models of colon cancer and melanoma.     

Multifunctional Nanoparticles Composed of A Poly( dl‐lactide‐coglycolide) Core and A Paramagnetic Liposome Shell for Simultaneous Magnetic Resonance Imaging and Targeted Therapeutics

A multifunctional nanoscale platform that is self‐assembled from a hydrophobic poly( dl ‐lactide‐coglycolide)(PLGA) core and a hydrophilic paramagnetic‐folate‐coated PEGylated lipid shell (PFPL; PEG=polyethylene glycol) is designed for simultaneous magnetic resonance imaging (MRI) and targeted therapeutics. The nanocomplex has a well‐defined core‐shell structure which is studied using confocal laser scanning microscopy (CLSM). The paramagnetic diethylenetriaminepentaacetic acid‐gadolinium (DTPA‐Gd) chelated to the shell layer exhibits significantly higher spin–lattice relaxivity (r₁) than the clinically used small‐molecular‐weight MRI contrast agent Magnevist^®. The PLGA core serves as a nanocontainer to load and release the hydrophobic drugs. From a drug‐release study, it is found that the modification of the PLGA core with a polymeric liposome shell can be a useful tool for reducing the drug‐release rate. Cellular uptake of folate nanocomplex is found to be higher than that of non‐folate‐nanocomplex due to the folate‐binding effect on the cell membrane. This work indicates that the multifunctional platform with combined characteristics applicable to MRI and drug delivery may have great potential in cancer chemotherapy and diagnosis.