# Macropinocytic Uptake and pH‐Responsive Endolysosomal Processing Drive Sustained Chemotherapeutic Efficacy of High‐Load Core@Shell Nanocarriers in Colorectal Cancer

## TL;DR

Researchers developed high-drug-load nanocarriers that improve chemotherapy by targeting colorectal cancer cells through a specific uptake and release mechanism.

## Contribution

The study introduces core@shell nanocarriers with a 57% drug load and demonstrates their pH-responsive drug release mechanism in cancer cells.

## Key findings

- Nanocarriers are taken up via macropinocytosis and release drugs in acidic endolysosomal compartments.
- The delayed drug release leads to prolonged cytotoxic effects in colorectal cancer cells.
- Probe-based imaging reveals the intracellular trafficking and nuclear delivery of nanocarrier cargo.

## Abstract

Poor tumor targeting, strong toxic side effects, and high drug resistance remain clinical challenges for conventional chemotherapy. Here, it is reported that drug‐cocktail core@shell nanocarriers are developed for the codelivery of lipophilic irinotecan (ITC) and the hydrophilic 5‐fluorouracil (5‐FU) metabolite (FdUMP), a commonly used combination in chemotherapy regimens for colorectal cancer. With a drug loading of 57% by mass, these nanocarriers achieve one of the highest reported drug payloads for a chemotherapeutic drug cocktail. Crucially, using a probe‐based imaging strategy with mechanistically responsive fluorescent reporters, we found that after slow uptake predominantly via macropinocytosis, the nanocarriers rapidly traffic to endolysosomal compartments, where the acidic environment triggers sustained drug release. In alignment with the slow uptake and trafficking behavior, these nanocarriers induce a delayed yet prolonged cytotoxic effect in colorectal cancer cells. These findings provide the first direct evidence linking slow uptake, intracellular trafficking, and progressive nuclear delivery of nanocarrier cargo to the delayed yet sustained cytotoxic response. Together, this work highlights both the therapeutic potential of these nanocarriers and the broad applicability of the probe‐based imaging approach to elucidate the mechanistic intracellular trafficking and nuclear delivery of different types of nanoparticles delivering cargoes beyond cancer chemotherapy in various cellular models.

This study develops core@shell nanocarriers with an exceptionally high chemotherapy drug payload, exhibiting strong cytotoxic effects. Using this adaptable nanocarrier‐synthesis platform, herein, the cellular uptake pathway and intracellular journey of the nanocarriers are elucidated with different probe‐based imaging strategies.© 2026 WILEY‐VCH GmbH