Tumor-targeted PROTAC prodrug nanoplatform enables precise protein degradation and combination cancer therapy.

Proteolysis targeting chimeras (PROTACs) have emerged as revolutionary anticancer therapeutics that degrade disease-causing proteins. However, the anticancer performance of PROTACs is often impaired by their insufficient bioavailability, unsatisfactory tumor specificity and ability to induce acquired drug resistance. Herein, we propose a polymer-conjugated PROTAC prodrug platform for the tumor-targeted delivery of the most prevalent von Hippel-Lindau (VHL)- and cereblon (CRBN)-based PROTACs, as well as for the precise codelivery of a degrader and conventional small-molecule drugs. The self-assembling PROTAC prodrug nanoparticles (NPs) can specifically target and be activated inside tumor cells to release the free PROTAC for precise protein degradation. The PROTAC prodrug NPs caused more efficient regression of MDA-MB-231 breast tumors in a mouse model by degrading bromodomain-containing protein 4 (BRD4) or cyclin-dependent kinase 9 (CDK9) with decreased systemic toxicity. In addition, we demonstrated that the PROTAC prodrug NPs can serve as a versatile platform for the codelivery of a PROTAC and chemotherapeutics for enhanced anticancer efficiency and combination benefits. This study paves the way for utilizing tumor-targeted protein degradation for precise anticancer therapy and the effective combination treatment of complex diseases.

Dual-targeting prodrug nanotheranostics for NIR-â ¡ fluorescence imaging-guided photo-immunotherapy of glioblastoma.

Glioblastoma (GBM) therapy is severely impaired by the blood-brain barrier (BBB) and invasive tumor growth in the central nervous system. To improve GBM therapy, we herein presented a dual-targeting nanotheranostic for second near-infrared (NIR-II) fluorescence imaging-guided photo-immunotherapy. Firstly, a NIR-Ⅱ fluorophore MRP bearing donor-acceptor-donor (D-A-D) backbone was synthesized. Then, the prodrug nanotheranostics were prepared by self-assembling MRP with a prodrug of JQ1 (JPC) and T7 ligand-modified PEG5k-DSPE. T7 can cross the BBB for tumor-targeted delivery of JPC and MRP. JQ1 could be restored from JPC at the tumor site for suppressing interferon gamma-inducible programmed death ligand 1 expression in the tumor cells. MRP could generate NIR-II fluorescence to navigate 808 nm laser, induce a photothermal effect to trigger in-situ antigen release at the tumor site, and ultimately elicit antitumor immunogenicity. Photo-immunotherapy with JPC and MRP dual-loaded nanoparticles remarkably inhibited GBM tumor growth in vivo. The dual-targeting nanotheranostic might represent a novel nanoplatform for precise photo-immunotherapy of GBM.

Engineered bioorthogonal POLY-PROTAC nanoparticles for tumour-specific protein degradation and precise cancer therapy.

PROteolysis TArgeting Chimeras (PROTACs) has been exploited to degrade putative protein targets. However, the antitumor performance of PROTACs is impaired by their insufficient tumour distribution. Herein, we present de novo designed polymeric PROTAC (POLY-PROTAC) nanotherapeutics for tumour-specific protein degradation. The POLY-PROTACs are engineered by covalently grafting small molecular PROTACs onto the backbone of an amphiphilic diblock copolymer via the disulfide bonds. The POLY-PROTACs self-assemble into micellar nanoparticles and sequentially respond to extracellular matrix metalloproteinase-2, intracellular acidic and reductive tumour microenvironment. The POLY-PROTAC NPs are further functionalized with azide groups for bioorthogonal click reaction-amplified PROTAC delivery to the tumour tissue. For proof-of-concept, we demonstrate that tumour-specific BRD4 degradation with the bioorthogonal POLY-PROTAC nanoplatform combine with photodynamic therapy efficiently regress tumour xenografts in a mouse model of MDA-MB-231 breast cancer. This study suggests the potential of the POLY-PROTACs for precise protein degradation and PROTAC-based cancer therapy.

Engineering Chameleon Prodrug Nanovesicles to Increase Antigen Presentation and Inhibit PD-L1 Expression for Circumventing Immune Resistance of Cancer.

Immune evasion is the major obstacle for T-cell-based cancer immunotherapy. The insufficient expression of the tumor-rejection antigen causes the intrinsic immune resistance and high expression of programmed death ligand 1 (PD-L1) induced by interferon gamma (IFN-γ), which accounts for the inducible immune resistance. To deal with both the intrinsic and inducible immune resistance of cancer, a multifunctional prodrug nanovesicle is sequentially developed. It is first sorted out that doxycycline (Doxy) efficiently inhibits autophagy of the tumor cells, and increases the surface level of major histocompatibility complex class I (MHC-I). Then, chameleon-inspired prodrug nanovesicles are engineered for tumor-targeted delivery of Doxy. The prodrug nanovesicles integrating a sheddable poly(ethylene glycol) shell and CRGDK ligand are kept stable during blood circulation, while exposing the targeting ligand in the tumor, which significantly inhibits autophagy, elicits MHC-I expression, increases tumor antigen presentation, recruits more tumor-infiltrating T lymphocytes, and suppresses FN-γ-induced intratumoral PD-L1 expression. After a proof of concept for overcoming intrinsic and inducible immune evasion, the prodrug nanovesicles are applied to validate the efficacy of cancer immunotherapy in two tumor-bearing mouse models. This research thus provides a novel targeting strategy for reducing tumor immune resistance and potentiating tumor immunotherapy.

Multifunctional peptide-assembled micelles for simultaneously reducing amyloid-ß and reactive oxygen species.

The excessive production and deposition of amyloid-ß (Aß) is one of the most important etiologies of Alzheimer's disease (AD). The interaction between Aß and metal ions produces aberrant reactive oxygen species (ROS), which induce oxidative stress and accelerate the progression of AD. To reduce Aß plaques and ROS to maintain their homeostasis is an emerging and ingenious strategy for effective treatment of AD. Herein, we report the rational design of multifunctional micelles (MPGLT) based on a polymer-grafted peptide to simultaneously clear Aß and ROS for AD therapy. The MPGLT integrating three functional peptides as a ROS scavenger (tk-GSH), ß-sheet breaker (LP) and an autophagy activator (TK) respectively, could capture and degrade Aß. Meanwhile, the tk-GSH on the surface of MPGLT effectively scavenges the intracellular ROS. Consequently, MPGLT reduced the cytotoxicity of Aß and ROS. In vivo animal studies using an AD mouse model further showed that MPGLT could transport across the blood-brain barrier for decreasing the Aß plaque and eliminating ROS in vivo. This peptide micelle-based synergistic strategy may provide novel insight for AD therapy.

Fluorescent metal-organic frameworks MIL-101(Al)-NH2 for rapid and sensitive detection of ellagic acid.

Ellagic acid (EA) is a symmetric natural phenol bioactive compound present in fruits and nuts, and has attracted substantial interest worldwide owing to its beneficial health effects. Here, the exploration of luminescent metal-organic frameworks (MOFs) of MIL-101(Al)-NH2 (MIL = Materials of Institute Lavoisier) for rapid and sensitive sensing of EA in aqueous solution was reported initially. The porous MIL-101(Al)-NH2 MOFs was synthesized by solvent-thermal method with inexpensive 2-aminoterephthalic acid and aluminum salt, which exhibited uniform spherical crystals (~340 nm) and specific mesoporous structure (3.2 nm). The fluorescence intensity of MIL-101(Al)-NH2 at 425 nm showed a good linear relationship with EA concentration in the range of 0.15-100 µM. The detection limit was as low as 43.8 nM, the rapid response time was within 2 min, and the cost of detection was low. In addition, the "turn off" fluorescence probe could be utilized for visual detection of EA according to the color change under the UV lamp. Based on the Stern-Volmer equation, the quenching constants was decreased with the rise of temperature, which indicated that the probable quenching mechanism was static quenching. The nanoprobe was successfully used to detect EA in the cherry and serum samples. MIL-101(Al)-NH2 represents the first instance of MOFs-based fluorescent probe in EA detection. This work not only enriches the detection method of EA, but also expands the potential application of MIL MOFs in small molecules.