C-1 Glycals serve as pivotal intermediates in synthesizing diverse C-glycosyl compounds and natural products, necessitating the development of concise, efficient and user-friendly methods to obtain C-1 glycosides is essential. The Suzuki-Miyaura cross-coupling of glycal boronates is notable for its reliability and non-toxic nature, but glycal donor stability remains a challenge. Herein, we achieve a significant breakthrough by developing stable glycal boronates, effectively overcoming the stability issue in glycal-based Suzuki–Miyaura coupling. Leveraging the balanced reactivity and stability of our glycal boronates, we establish a robust palladium-catalyzed glycal-based Suzuki-Miyaura reaction, facilitating the formation of various C(sp²)-C(sp), C(sp²)-C(sp²), and C(sp²)-C(sp³) bonds under mild conditions. Notably, we expand upon this achievement by developing the DNA-compatible glycal-based cross-coupling reaction to synthesize various glycal-DNA conjugates. With its excellent reaction reactivity, stability, generality, and ease of handling, the method holds promise for widespread appication in the preparation of C-glycosyl compounds and natural products.

P-glycoprotein (P-gp) induced multidrug resistance (MDR) is the main reason for the failure of cancer chemotherapy. The combined delivery of chemodrug and P-gp inhibitor is a promising pathway to reverse MDR. However, the intrinsic stimuli in the tumor microenvironment could not realize a complete drug release, which would induce poor cancer therapeutic efficacy. Herein, we conjugated tamoxifen (TAM) with D-α-tocopherol polyethylene glycol1000 succinate (TPGS) based on a reactive oxygen species (ROS)-responsive aryl boronic ester bond to construct a self-amplified ROS-responsive chemodrug–inhibitor (TPGS–TAM) co-delivery system. Due to its amphiphilic property, the TPGS–TAM conjugates could self-assemble into uniform spherical nanoparticles (NPs). After effective endocytosis by cancer cells, the intracellular ROS cleaved the aryl boronic ester bond and initiated the release of TAM and α-tocopherol succinate (α-TOS) from the NPs. Subsequently, the released α-TOS further generated ROS to facilitate the release of TAM. Moreover, α-TOS also consumed adenosine triphosphate (ATP) to impair ATP-dependent P-gp mediated drug efflux to reverse the tumor's drug resistance. As a result, the TPGS–TAM NPs enhanced the antitumor effect with a tumor inhibition rate (TIR) high up to 74.6 ± 6.1% in an MCF-7/ADR tumor model. Based on systematic in vitro and in vivo assessments, this self-amplified ROS-responsive carrier-free conjugate of chemodrug/P-gp inhibitor may shed light on the potential application for the MDR cancer therapy.

The combination of gene therapy and chemotherapy is emerging as a promising strategy for multidrug-resistant (MDR) cancer treatment. However, due to the significant differences in the physicochemical properties between macromolecular oligonucleotides and chemodrugs, the co-delivery of different drug combos makes for a great challenge. Moreover, the biosafety of the carriers and poor lysosomal escape of oligonucleotides are the main concerns for combination therapy. Herein, we developed a facile carrier-free strategy to co-deliver small interfering RNA (siRNA) and positive-charged chemodrugs (termed cationic amphiphilic chemodrugs, CACDs), in which CACDs interact with negative-charged anti P-glycoprotein siRNA (siPgp) without extra carriers and self-assemble into siPgp/CACDs nanoparticles (NPs_{[siPgp/CACDs]}). Meanwhile, the CACDs also play an important role in the lysosomal escape of siRNA. Both molecular dynamics simulations and experimental characterization demonstrate that CACDs and siRNA can self-assemble into nanoparticles. Furthermore, red blood cell membrane (RBCm) was used to camouflage the NPs_{[siPgp/CACDs]} to enhance their physiological stability and prolong the circulation time. Both in vitro and in vivo assessments reveal their excellent performance for drug-resistant cancer treatment. This strategy provides a safe and efficient pathway for gene and chemo combination therapy for MDR cancers.

The β-barrel structure of green fluorescent protein (GFP) provides a confined environment to enhance its fluorescence efficiency. Inspired by the unique structure of GFP, we reported a self-restricted GFP chromophore analogue which was rationally grafted onto the middle or the terminal of poly(ethylene glycol)-block-poly(N-isopropyl acrylamide) (PEG-b-PNIPAM) via click chemistry to obtain PEG-GA-PNIPAM and PEG-PNIPAM-GA (GA: MeOBDPI). These structures were characterized through NMR, GPC, and FT-IR. By varying the length of PNIPAM and the location of the GFP chromophore, self-assembly behaviour and fluorescence intensity were correspondingly changed. PEG-GA-PNIPAM and PEG-PNIPAM-GA were assembled into nano-sized spherical micelles above the low critical solution temperature (LCST). The size of the micelles increased with the length of the PNIPAM block. These optical properties were carefully evaluated by UV-Vis and fluorescence spectroscopy. The results indicated that increasing the length of the PNIPAM block enhanced the fluorescence in water, and PEG-PNIPAM₇₄-GA has more remarkable fluorescence intensity than PEG-GA-PNIPAM₁₀₆ in living cells such as MCF-7 cells. Furthermore, the fluorescence behaviour of PEG-PNIPAM₇₄-GA was studied in MCF-7 cells and L929 cells. The result showed that PEG-PNIPAM₇₄-GA was mostly located in the cytoplasm. Compared with the CellTracker™ Red CMTPX dye, it could enter into MCF-7 cells and L929 cells more easily in DMEM with 10% FBS. Therefore, PEG-PNIPAM₇₄-GA has potential application prospects for living cell imaging.