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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 lysosomal-targeting self-condensation prodrug-nanoplatform (

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.

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

Peptide drug conjugate (PDC) has emerged as one of the new generations of targeted therapeutics for cancer, which owns the advantages of improved drug targetability and reduced adverse effects compared with traditional chemotherapy. However, the poor permeability of PDC drugs regarding tumor cells is an urgent problem to be solved. Herein, we design a PDC drug molecule, which is composed of three modules: targeting motif (RGD target), assembly motif (GNNNQNY) and cytotoxic payload (CPT molecule). This PDC in situ forms nanoclusters upon binding cellular receptor, resulting in improved PDC cell-entry efficiency and treatment efficacy. In addition, the PDC shows increased therapeutic efficacy and raises the maximum tolerance dose of the drug in breast and bladder xenografted mice models. This strategy leverages the assembly principle to promote penetration of peptide molecules into cells and increase intracellular drug bioavailability, which is of great significance for the development of PDC drugs in the future.