Bioengineered "Molecular Glue"-Mediated Tumor-Specific Cascade Nanoreactors with Self-Destruction Ability for Enhanced Precise Starvation/Chemosynergistic Tumor Therapy.

The ordered and directed functionalization of targeting elements on the surface of nanomaterials for precise tumor therapy remains a challenge. To address the above problem, herein, we adopted a materials-based synthetic biotechnology strategy to fabricate a bioengineered fusion protein of materials-binding peptides and targeting elements, which can serve as a "molecular glue" to achieve a directional and organized assembly of targeting biological macromolecules on the surface of nanocarriers. The hypoxia microenvironment of solid tumors inspired the rapid development of starvation/chemosynergistic therapy; however, the unsatisfied spatiotemporal specific performance hindered its further development in precise tumor therapy. As a proof of concept, a bioengineered fusion protein containing a dendritic mesoporous silicon (DMSN)-binding peptide, and a tumor-targeted and acidity-decomposable ferritin heavy chain 1 (FTH1), was constructed by fusion expression and further assembled on the surface of DMSN companying with the insertion of hypoxia-activated prodrug tirapazamine (TPZ) and glucose oxidase (GOX) to establish a nanoreactor for precise starvation/chemosynergistic tumor therapy. In this context, the as-prepared therapeutic nanoreactors revealed obvious tumor-specific accumulation and an endocytosis effect. Next, the acidic tumor microenvironment triggered the structural collapse of FTH1 and the subsequent release of GOX and TPZ, in which GOX-mediated catalysis cut off the nutrition supply to realize starvation therapy based on the consumption of endogenous glucose and further provided an exacerbated hypoxia environment for TPZ in situ activation to initiate tumor chemotherapy. More significantly, the presence of "molecular glue" elevated the tumor-targeting capacity of nanoreactors and further enhanced the starvation/chemosynergistic therapeutic effect remarkably, suggesting that such a strategy provided a solution for the functionality of nanomaterials and facilitated the design of novel targeting nanomedicines. Overall, this study highlights materials-binding peptides as a new type of "molecular glue" and opens new avenues for designing and exploring active biological materials for biological functions and applications.

Tumor targeting antibody-conjugated nanocarrier with pH/thermo dual-responsive macromolecular film layer for enhanced cancer chemotherapy.

In response to changeful tumor environment, self-targeting antibody-mediated drug nanocarrier with functionalization have been broadly developed to realize specific antitumor efficacy. In this work, an antibody-conjugated drug delivery system with pH/temperature dual-responsive property was devised and fabricated based on mesoporous silica nanoparticle (MSN). Briefly, MSN was first modified with the pH/temperature dual-responsive macromolecular copolymer P(NIPAm-co-MAA) via a precipitation polymerization method, and then grafted with the anti-human epidermal growth factor receptor 2 (HER2) single chain antibody fragment (scFv) to specifically target HER2 positive breast cancer cells. With this structure, such targeting nanoparticles eventually exhibited high drug loading capacity and good biocompatibility. Meanwhile, the cumulative in vitro drug release profile displayed a low-level early leakage at neutral pH values/low temperature while remarkably enhanced release at an acidic pH value/high temperature, indicating an apparent pH/temperature-triggered drug release pattern. Moreover, tumor-targeting assay revealed that the anti-HER2 scFv-surface decoration greatly enhanced the cellular uptake of as-prepared nanoparticle through HER2-antibody-mediated endocytosis, as well as improved the uptake selectivity between normal and cancer cells. More importantly, both the in vitro and in vivo anticancer experiments indicated that such targeting dual-responsive nanoplatform could efficiently inhibit the growth of HER2 positive breast cancer with minimal side effects. Collectively, all these results promised such specific-targeted and dual-responsive nanoparticle a smart drug delivery system, and it provided a promising perspective in efficient and controllable cancer therapeutic application.

Reversibly-regulated drug release using poly(tannic acid) fabricated nanocarriers for reduced secondary side effects in tumor therapy.

Numerous nanocarriers with pH-responsive properties have been designed and fabricated to reduce the adverse side effects of traditional chemotherapeutics, but these traditional nanocarriers are rarely reversible; this may cause "secondary" side effects on normal tissues, because the nanocarriers cannot be sealed again to prevent the leakage of incompletely released drugs after re-entering blood circulation. To overcome these limitations, we report herein the synthesis of a reversibly pH-responsive drug delivery system, which can achieve regulated drug release in a "release-stop-release" manner corresponding to changes in pH. Specifically, poly(tannic acid) as the "gatekeeper" was firstly deposited and polymerized on the surface of mesoporous silica nanoparticles (MSNs) via a modified mussel-inspired method similar to dopamine, and the formed polymer shell can be easily decorated with a targeting ligand HER2 antibody for the selective delivery of drugs to specific cells. The resulting nanocomposites exhibited good colloidal stability, good biocompatibility, high drug loading capacity and accurate HER2 antibody mediated targeting ability. Interestingly, a series of experiments fully demonstrated that the fabricated nanocomposites possessed intelligent reversible pH-responsive controlled release behavior through adjusting the density of the "gatekeeper" under different pH conditions, thereby achieving reversible switching from "on" to "off". Furthermore, in vitro and in vivo experiments verified that the fabricated targeting nanoparticles could efficiently inhibit tumor growth with minimal side effects. Meanwhile, these nanocarriers exhibited excellent reusability, in vitro cytotoxicity and minimal in vivo myocardial damage. Collectively, the reversible pH-operated nanovalve on the MSNs constructed here could serve as a nanoplatform to solve the problem of "secondary" side effects caused by residual drugs in irreversible "gatekeeper" systems.

Laccase-immobilized tannic acid-mediated surface modification of halloysite nanotubes for efficient bisphenol-A degradation.

Halloysite nanotubes (HNTs) have been pursued as promising carriers for enzyme immobilization, but the lack of functional groups severely limits their applications. Herein, we reported a simple tannic acid (TA)-mediated surface modification strategy for the fabrication of HNT-based efficient enzyme immobilization supports. Particularly, TA was first self-polymerized and deposited onto the surface of HNTs to form a thin active film via a mussel-inspired method, and the model enzyme laccase was directly conjugated via the Michael addition and/or Schiff base condensation between quinone groups on poly(tannic acid) layer surfaces and exposed amine groups on laccase surfaces. Under the optimum conditions, this newly fabricated support retained good enzyme-loading and activity recovery properties with 197.9 mg protein per gram of support and 55.4% of activity recovery being achieved. In addition, this immobilized laccase was less influenced by pH, temperature, and inhibitor changes and exhibited higher storage stability than free laccases as more than 70% of initial activity was retained by the immobilized laccase, while less than 30% was retained for free laccase after one-month storage at 4 °C. Finally, a higher bisphenol-A (BPA) removal efficiency and more reuse cycles were demonstrated for immobilized laccases. As a result, this TA-mediated surface modification is a simple and green method for biological macromolecule immobilization on HNTs in one step.