No abstract

The morphology controlled molecular assemblies play vital roles in biological systems. Here we present endogenous reactive oxygen species (ROS)triggered morphology transformation of polymer−peptide conjugates (PPCs) for cooperative interaction with mitochondria, exhibiting high tumor therapeutic efficacy. The PPCs are composed of (i) a β-sheet-forming peptide KLVFF conjugated with poly(ethylene glycol) through ROS-cleavable thioketal, (ii) a mitochondria-targeting cytotoxic peptide KLAK, and (iii) a poly(vinyl alcohol) backbone. The self-assembled PPCs nanoparticles can enter cells and target mitochondria. Because of overgenerated ROS around mitochondria in most cancer cells, the thioketal linker can be cleaved, leading to transformation from nanoparticles to fibrous nanostructures. As a result, the locational nanofibers with exposure of KLAK exhibit enhanced multivalent cooperative interactions with mitochondria, which causes selective cytotoxicity against cancer cells and powerful tumor suppression efficacy in vivo. As the first example of ROStriggered intracellular transformation, the locational assembly strategy in vivo may provide a new insight for disease diagnosis and therapy through enhanced interaction with targeting site.

Background Clear cell renal cell carcinoma (CCRCC) is characterized by a highly metastatic potential. The stromal communication between stem cells and cancer cells critically influences metastatic dissemination of cancer cells. Methods The effect of exosomes isolated from cancer stem cells (CSCs) of CCRCC patients on the progress of epithelial-mesenchymal transition (EMT) and lung metastasis of CCRCC cells were examined. Results CSCs exosomes promoted proliferation of CCRCC cells and accelerated the progress of EMT. Bioactive miR-19b-3p transmitted to cancer cells by CSC exosomes induced EMT via repressing the expression of PTEN. CSCs exosomes derived from CCRCC patients with lung metastasis produced the strongest promoting effect on EMT. Notably, CD103+ CSC exosomes were enriched in tumor cells and in lung as well, highlighting the organotropism conferred by CD103. In addition, CD103+ exosomes were increased in blood samples from CCRCC patients with lung metastasis. Conclusions CSC exosomes transported miR-19b-3p into CCRCC cells and initiated EMT promoting metastasis. CD103+ acted to guide CSC exosomes to target cancer cells and organs, conferring the higher metastatic capacity of CCRCC to lungs, suggesting CD103+ exosomes as a potential metastatic diagnostic biomarker. Graphical abstract ᅟ

Achieving the activation of drugs within cellular systems may provide targeted therapies. Here we construct a tumour-selective cascade activatable self-detained system (TCASS) and incorporate imaging probes and therapeutics. We show in different mouse models that the TCASS system accumulates in solid tumours. The molecules show enhanced accumulation in tumour regions via the effect of recognition induced self-assembly. Analysis of the molecular penetration in tumour tissue shows that in vivo self-assembly increases the penetration capability compared to typical soft or hard nanomaterials. Importantly, the in vivo self-assembled molecules exhibit a comparable clearance pathway to that of small molecules, which are excreted from organs of the reticuloendothelial system (liver and kidney), while are relatively slowly eliminated from tumour tissues. Finally, this system, combined with the NIR probe, shows high specificity and sensitivity for detecting bladder cancer in isolated intact patient bladders.

Image-guided surgery plays a crucial role in realizing complete tumor removal, reducing postoperative recurrence and increasing patient survival. However, imaging of tumor lesion in the typical metabolic organs, e.g., kidney and liver, still has great challenges due to the intrinsic nonspecific accumulation of imaging probes in those organs. Herein, we report an in situ self-assembled near-infrared (NIR) peptide probe with tumor-specific excretion-retarded (TER) effect in tumor lesions, enabling high-performance imaging of human renal cell carcinoma (RCC) and achieving complete tumor removal, ultimately reducing postoperative recurrence. The NIR peptide probe first specifically recognizes αvβ3 integrin overexpressed in renal cancer cells, then is cleaved by MMP-2/9, which is up-regulated in the tumor microenvironment. The probe residue spontaneously self-assembles into nanofibers that exhibit an excretion-retarded effect in the kidney, which contributes to a high signal-to-noise (S/N) ratio in orthotopic RCC mice. Intriguingly, the TER effect also enables precisely identifying eye-invisible tiny lesions (<1 mm), which contributes to complete tumor removal and significantly reduces the postoperative recurrence compared with traditional surgery. Finally, the TER strategy is successfully employed in high-performance identification of human RCC in an ex vivo kidney perfusion model. Taken together, this NIR peptide probe based on the TER strategy is a promising method for detecting tumors in metabolic organs in diverse biomedical applications.

Chemotherapy has been validated unavailable for treatment of renal cell carcinoma (RCC) in clinic due to its intrinsic drug resistance. Sensitization of chemo‐drug response plays a crucial role in RCC treatment and increase of patient survival. Herein, a recognition‐reaction‐aggregation (RRA) cascaded strategy is utilized to in situ construct peptide‐based superstructures on the renal cancer cell membrane, enabling specifically perturbing the permeability of cell membranes and enhancing chemo‐drug sensitivity in vitro and in vivo. First, P1‐DBCO can specifically recognize renal cancer cells by targeting carbonic anhydrase IX. Subsequently, P2‐N3 is introduced and efficiently reacts with P1‐DBCO to form a peptide P3, which exhibits enhanced hydrophobicity and simultaneously aggregates into a superstructure. Interestingly, the superstructure retains on the cell membrane and perturbs its integrity/permeability, allowing more doxorubicin (DOX) uptaken by renal cancer cells. Owing to this increased influx, the IC50 is significantly reduced by nearly 3.5‐fold compared with that treated with free DOX. Finally, RRA strategy significantly inhibits the tumor growth of xenografted mice with a 3.2‐fold enhanced inhibition rate compared with that treated with free DOX. In summary, this newly developed RRA strategy will open a new avenue for chemically engineering cell membranes with diverse biomedical applications.

Photodynamic therapy (PDT) has shown great potential in infection treatment. However, the shallow depth of the short wavelength light and the low reactive oxygen species (ROS) production hinder its development. A strategy that can achieve a second near-infrared (NIR-II) light that is a long wavelength induced multi-intensified antibacterial PDT is most critical. Herein, hybrid plasmonic Au/CdSe x S y with precise Ag doping (ACA) nanodumbbells are rationally designed for ideal NIR-II light induced antibacterial PDT. Plasmonic Au nanorods extend the photocatalytic activity of ACA to NIR-II regions, which provides a basis for NIR-II light induced PDT. More importantly, multi-intensified PDT can be realized by the following creativities: (i) elaborate design of as-synthesized nanodumbbells that allows for electron holes to be redistributed in different regions simultaneously, (ii) the efficient hot-electrons injection that benefits from the ratio tailoring of anions ratio of Se and S, and (iii) the dopant Ag level inhibiting the combination of electron holes. The nanodumbbells create effective hot-electrons injection and a separation of electron holes, which provides great convenience for the production of ROS and allows NIR-II light induced PDT for the inhibition of bacteria and biofilms. As a result, comparably, our well-defined ACA hybrid nanodumbbells can generate about 40-fold superoxide radicals (·O2 –) and more hydroxyl radicals (·OH). Therefore, the MIC value of the as-synthesized nanodumbbells is lower than the value of 1/16 of core–shell ACA. In vivo results further demonstrate that our nanodumbbells exhibit excellent PDT efficacy.

The fabrication of functional assemblies with defined structures through controllable molecular packing under physiological conditions is challenging.Here,modularly designed peptide-cyanine conjugates that intracellularly selfassembly into 1D columnar superstructures with controlled cyanine aggregation were designed, and they exhibit distinct imaging or photothermal properties.T he peptide backbone is cleaved by caspase-3/7 after entering the cells.T hen the selfassembled residue,w ith ad ouble cyanine substitution (Pr-2Cy), forms aPhelical column in which H-aggregated cyanine dyes show 3.4-fold photothermal conversion efficiency compared to free ones.T he self-assembled residue with as ingle cyanine substitution (Pr-1Cy)forms aloose column, in which cyanine dyes with undefined structure have af luorescence quantum yield of up to 9.5 %(emission at 819 nm in H 2 O). This work provides as imple wayt om odify in vivo selfassembled peptides with functional molecules for achieving desired bio-applications.