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The study offers deep insights about the intratumoral barriers that hinder the active-targeted nanoparticles delivery, and provides a basis for developing more effective strategies to accelerate the clinical translation of active-targeted nanomedicines.A genetically encoded caffeine-operated synthetic module (COSMO) is introduced herein as a robust chemically induced dimerization (CID) system. COSMO enables chemogenetic manipulation of biological processes by caffeine and its metabolites, as well as caffeinated beverages, including coffee, tea, soda, and energy drinks. This CID tool, evolved from an anti-caffeine nanobody via cell-based high-throughput screening, permits caffeine-inducible gating of calcium channels, tumor killing via necroptosis, growth factors-independent activation of tyrosine receptor kinase signaling, and enhancement of nanobody-mediated antigen recognition for the severe acute respiratory distress coronavirus 2 (SARS-CoV-2) spike protein. Further rationalized engineering of COSMO leads to 34-217-fold enhancement in caffeine sensitivity (EC50 = 16.9 nanomolar), which makes it among the most potent CID systems like the FK506 binding protein (FKBP)-FKBP rapamycin binding domain (FRB)-rapamycin complex. Furthermore, bivalent COSMO (biCOMSO) connected with a long linker favors intramolecular dimerization and acts as a versatile precision switch when inserted in host proteins to achieve tailored function. Given the modularity and high transferability of COMSO and biCOSMO, these chemical biology tools are anticipated to greatly accelerate the development of therapeutic cells and biologics that can be switched on and off by caffeinated beverages commonly consumed in the daily life.A highly periodic electrostatic potential, even though established in van der Waals bonded organic crystals, is essential for the realization of a coherent band electron system. While impurity doping is an effective chemical operation that can precisely tune the energy of an electronic system, it always faces an unavoidable difficulty in molecular crystals because the introduction of a relatively high density of dopants inevitably destroys the highly ordered molecular framework. In striking contrast, a versatile strategy is presented to create coherent 2D electronic carriers at the surface of organic semiconductor crystals with their precise molecular structures preserved perfectly. The formation of an assembly of redox-active molecular dopants via a simple one-shot solution process on a molecularly flat crystalline surface allows efficient chemical doping and results in a relatively high carrier density of 1013 cm-2 at room temperature. Structural and magnetotransport analyses comprehensively reveal that excellent carrier transport and piezoresistive effects can be obtained that are similar to those in bulk crystals.In order to solve the problems of receptor promiscuity and poor blood-brain barrier (BBB) penetration in the treatment of glioblastomas (GBM), a novel dual-functional nanocomplex drug delivery system is developed based on the strategy of peptide-drug conjugates. [https://www.selleckchem.com/products/dc661.html DC661] In this study, SynB3-PVGLIG-PTX is designed and screened out by matrix metalloproteinase-2 (MMP-2), to which it exhibits the best affinity. The MMP-2-sensitive peptide (PVGLIG) and a cell-penetration peptide (SynB3) are combined to form a dual-functional peptide. Moreover, as a drug-peptide nanocomplex, SynB3-PVGLIG-PTX exhibited a high potential to form an aggregation with good solubility that can release paclitaxel (PTX) through the cleavage of MMP-2. From a functional perspective, it is found that SynB3-PVGLIG-PTX can specifically inhibit the proliferation, migration, and invasion of GBM cells in vitro in the presence of MMP-2, in contrast to that observed in MMP-2 siRNA transfected cells. Further investigation in vivo shows that SynB3-PVGLIG-PTX easily enters the brain of U87MG xenograft nude mice and can generate a better suppressive effect on GBM through a controlled release of PTX from SynB3-PVGLIG-PTX compared with PTX and temozolomide. Thus, it is proposed that SynB3-PVGLIG-PTX can be used as a novel drug-loading delivery system to treat GBM due to its specificity and BBB permeability.Nano-immunotherapy regimens have high potential to improve patient outcomes, as already demonstrated in advanced triple negative breast cancer with nanoparticle albumin-bound paclitaxel and the immune checkpoint blocker (ICB) atezolizumab. This regimen, however, does not lead to cures with median survival lasting less than two years. Thus, understanding the mechanisms of resistance to and development of strategies to enhance nano-immunotherapy in breast cancer are urgently needed. Here, in human tissue it is shown that blood vessels in breast cancer lung metastases are compressed leading to hypoxia. This pathophysiology exists in murine spontaneous models of triple negative breast cancer lung metastases, along with low levels of perfusion. Because this pathophysiology is consistent with elevated levels of solid stress, the mechanotherapeutic tranilast, which decompressed lung metastasis vessels, is administered to mice bearing metastases, thereby restoring perfusion and alleviating hypoxia. As a result, the nanomedicine Doxil causes cytotoxic effects into metastases more efficiently, stimulating anti-tumor immunity. Indeed, when combining tranilast with Doxil and ICBs, synergistic effects on efficacy, with all mice cured in one of the two ICB-insensitive tumor models investigated is resulted. These results suggest that strategies to treat breast cancer with nano-immunotherapy should also include a mechanotherapeutic to decompress vessels.One of the well-known strategies for achieving high-performance light-activated gas sensors is to design a nanostructure for effective surface responses with its geometric advances. However, no study has gone beyond the benefits of the large surface area and provided fundamental strategies to offer a rational structure for increasing their optical and chemical performances. Here, a new class of UV-activated sensing nanoarchitecture made of highly periodic 3D TiO2, which facilitates 55 times enhanced light absorption by confining the incident light in the nanostructure, is prepared as an active gas channel. The key parameters, such as the total 3D TiO2 film and thin-shell thicknesses, are precisely optimized by finite element analysis. Collectively, this fundamental design leads to ultrahigh chemoresistive response to NO2 with a theoretical detection limit of ≈200 ppt. The demonstration of high responses with visible light illumination proposes a future perspective for light-activated gas sensors based on semiconducting oxides.