Precise and effective manipulation of protein functions still faces tremendous challenges. Herein we report a programmable peptide molecule, consisted of targeting and self-assembly modules, that enables specific and highly efficient assembly governed by targeting receptor proteins. Upon binding to the cell membrane receptor, peptide conformation is somewhat stabilized along with decreased self-assembly activation energy, promoting peptide-protein complex oligomerization. We first design a GNNQQNY-RGD peptide (G7-RGD) to recognize integrin α V β 3 receptor for proof-of-concept study. In the presence of α V β 3 protein, the critical assembly concentration of free G7-RGD decreases from 525 to 33 μM and the resultant G7-RGD cluster drives integrin receptor oligomerization. Finally, a bispecific assembling peptide antiCD3-G7-RGD is rationally designed for cancer immunotherapy, which validates CD3 oligomerization and concomitant T cell activation, leading to T cell-mediated cancer cell cytolysis.

No abstract

Proteolysis targeting chimera (PROTAC) is an emerging pharmacological modality with innovated post‐translational protein degradation capabilities. However, off‐target induced unintended tissue effects and intrinsic “hook effect” hinder PROTAC biotechnology to be maturely developed. Herein, an intracellular fabricated nano proteolysis targeting chimeras (Nano‐PROTACs) modality with a center‐spoke degradation network for achieving efficient dose‐dependent protein degradation in tumor is reported. The PROTAC precursors are triggered by higher GSH concentrations inside tumor cells, which subsequently in situ self‐assemble into Nano‐PROTACs through intermolecular hydrogen bond interactions. The fibrous Nano‐PROTACs can form effective polynary complexes and E3 ligases degradation network with multi‐binding sites, achieving dose‐dependent protein degradation with “anti‐hook effect”. The generality and efficacy of Nano‐PROTACs are validated by degrading variable protein of interest (POI) such as epidermal growth factor receptor (EGFR) and androgen receptor (AR) in a wide‐range dose‐dependent manner with a 95 % degradation rate and long‐lasting potency up to 72 h in vitro. Significantly, Nano‐PROTACs achieve in vivo dose‐dependent protein degradation up to 79 % and tumor growth inhibition in A549 and LNCap xenograft mice models, respectively. Taking advantages of in situ self‐assembly strategy, the Nano‐PROTACs provide a generalizable platform to promote precise clinical translational application of PROTAC.

Intravesical administration of first‐line drugs has shown failure in the treatment of bladder cancer owing to the poor tumor retention time of chemotherapeutics. Herein, we report an intracellular hydrolytic condensation (IHC) system to construct long‐term retentive nano‐drug depots in situ, wherein sustained drug release results in highly efficient suppression of bladder cancer. Briefly, the designed doxorubicin (Dox)‐silane conjugates self‐assemble into silane‐based prodrug nanoparticles, which condense into silicon particle‐based nano‐drug depots inside tumor cells. Significantly, we demonstrate that the IHC system possesses highly potent antitumor efficacy, which leads to the regression and eradication of large established tumors and simultaneously extends the overall survival of air pouch bladder cancer mice compared with that of mice treated with Dox. The concept of intracellular hydrolytic condensation can be extended via conjugating other chemotherapeutic drugs, which may facilitate rational design of novel nanomedicines for augmentation of chemotherapy.

Lysosome-targeting self-assembling prodrugs had emerged as an attractive approach to overcome the acquisition of resistance to chemotherapeutics by inhibiting lysosomal sequestration. Taking advantage of lysosomal acidification induced intracellular hydrolytic condensation, we developed a lysosomaltargeting self-condensation prodrug-nanoplatform (LTSPN) system for overcoming lysosome-mediated drug resistance. Briefly, the designed hydroxycamptothecine (HCPT)-silane conjugates self-assembled into silane-based nanoparticles, which were taken up into lysosomes by tumor cells. Subsequently, the integrity of the lysosomal membrane was destructed because of the acid-triggered release of alcohol, wherein the nanoparticles self-condensed into silicon particles outside the lysosome through intracellular hydrolytic condensation. Significantly, the LTSPN system reduced the half-maximal inhibitory concentration (IC 50 ) of HCPT by approximately 4 times. Furthermore, the LTSPN system realized improved control of large established tumors and reduced regrowth of residual tumors in several drug-resistant tumor models. Our findings suggested that target destructing the integrity of the lysosomal membrane may improve the therapeutic effects of chemotherapeutics, providing a potent treatment strategy for malignancies.

No abstract

Up to 75% of bladder cancer patients suffer from recurrence due to postoperative tumor implantation. However, clinically used Bacillus Calmette-Guerin (BCG) treatment failed to inhibit the recurrence. Here, we report a bispecific glycopeptide (bsGP) that simultaneously targets CD206 on tumor-associated macrophages (TAMs) and CXCR4 on tumor cells. bsGP repolarizes protumoral M2-like TAMs to antitumor M1-like that mediated cytotoxicity and T cell recruitment. Meanwhile, bsGP is cleaved by the MMP-2 enzyme to form nanostructure for the long-term inhibition of CXCR4 downstream signaling, resulting in reduced tumor metastasis and promoted T cell infiltration. In orthotopic bladder tumor models, bsGP reduced the postoperative recurrence rate to 22%. In parallel, the recurrence rates of 89 and 78% were treated by doxycycline and BCG used in clinic, respectively. Mechanistic studies reveal that bsGP reduces the matrix microenvironment barrier, increasing the spatially redirected CD8 + T cells to tumor cells. We envision that bis-targeting CD206 and CXCR4 may pave the way to inhibit tumor metastasis and recurrence.

Anti‐PD‐L1 monoclonal antibody (mAb) has achieved substantial success in tumor immunotherapy by T‐cells activation. However, owing to the excessive accumulation of extracellular matrix (ECM) components induced unsatisfactory T‐cells infiltration and poor tumor penetration of antibodies makes it challenging to realize efficient tumor immunotherapy. Herein, we reported a peptide‐based bispecific nano‐blocker (BNB) strategy for in situ construction of CXCR4/PD‐L1 targeted nanoclusters on the surface of tumor cells that capable of boosting up T‐cells infiltration through CXCR4 blockage and enhancing T‐cells activation by PD‐L1 occupancy, ultimately realizing high‐performance tumor immunotherapy. Briefly, the BNB strategy selectively recognize and bond CXCR4/PD‐L1 with deep tumor penetration, which rapidly self‐assembles into nanoclusters on the surface of tumor cells. Compared to the traditional bispecific antibody, BNB exhibits an intriguing metabolic behavior, i.e., the elimination half‐life (t1/2) of BNB in the tumor is 69.3 h that is about 50‐time longer than that in the plasma (1.4 h). The higher tumor accumulation and rapid systemic clearance overcomes potential systemic side effect. Moreover, the solid tumor stress generated by excessive extracellular matrix components is substantially reduced to 44%, which promotes T‐cells infiltration and activation for immunotherapy efficacy. Finally, our findings substantially strengthen and extend clinical applications of PD‐1/PD‐L1 immunotherapy.This article is protected by copyright. All rights reserved