Intracellular Condensates of Oligopeptide for Targeting Lysosome and Addressing Multiple Drug Resistance of Cancer

TLDR

Biomolecular condensates are ubiquitous in biology and regulate cellular functions, yet designing functional artificial condensates with precise spatiotemporal control remains challenging. The study presents a general strategy to build lysosome‑targeted biomolecular condensates (hydrogels) in living cancer cells to counteract lysosome‑mediated drug sequestration and multidrug resistance. The approach uses an aromatic‑motif‑appended, pH‑responsive hexapeptide derived from insulin that is internalized via caveolae‑dependent endocytosis and undergoes proton‑triggered phase transition from solution to hydrogel within the lysosome. Lysosomal hydrogelation enlarges lysosomes, increases permeability, induces cancer cell death, and markedly enhances chemotherapy efficacy in multidrug‑resistant cells in vitro and in xenograft models, demonstrating a new strategy to overcome MDR.

Abstract

Biomolecular condensates have been demonstrated as a ubiquitous phenomenon in biological systems and play a crucial role in controlling cellular functions. However, the spatiotemporal construction of artificial biomolecular condensates with functions remains challenging and has been less explored. Herein, a general approach is reported to construct biomolecular condensates (e.g., hydrogel) in the lysosome of living cells for cancer therapy and address multiple drug resistance induced by lysosome sequestration. Aromatic-motif-appended pH-responsive hexapeptide (LTP) derived from natural insulin can be uptaken by cancer cells mainly through caveolae-dependent endocytosis, ensuring the proton-triggered phase transformation (solution to hydrogel) of LTP inside the lysosome specifically. Lysosomal hydrogelation further leads to enlargement of the lysosome in cancer cells and increases the permeability of the lysosome, resulting in cancer cell death. Importantly, lysosomal assemblies can significantly improve the efficiency of current chemotherapy drugs toward multidrug resistance (MDR) cells in vitro and in xenograft tumor models. As an example of functional artificial condensates in lysosomes, this work provides a new strategy for controlling functional condensates formation precisely in the organelles of living cells and addressing MDR in cancer therapy.