Innovative Nanoparticle Strategies in Targeting MSS Colorectal Cancer: pH-Responsive Systems and Their Translational Potential

pH‑responsive solid lipid nanoparticles enable tumor‑selective delivery and immune reprogramming in microsatellite‑stable (MSS) colorectal cancer, converting immune‑excluded tumors into T cell–permissive microenvironments. In preclinical models these nanoparticles showed tumor‑preferential payload release with associated antitumor activity, supporting translational evaluation; the data inform biomarker‑driven early‑phase strategies.

The formulation is a pH-responsive solid lipid nanoparticle coated with a PEG–PGA layer that detaches in acidic tumor niches to expose targeting ligands. PD‑L1– and EGFR‑binding peptides on the particle surface direct selective uptake by tumor cells and tumor‑associated macrophages, and an ER‑homing peptide biases subcellular localization to the endoplasmic reticulum. The platform co‑delivers a PD‑L1–targeting microRNA (miR‑142), a TLR7 agonist (imiquimod), and a VCP inhibitor to induce localized ER stress. Measured endpoints included quantitative tumor accumulation, biochemical and histologic ER stress markers, and evidence of PD‑L1 suppression and receptor engagement in preclinical CRC models; together these features produced spatially confined, tumor‑selective payload release in the reported experiments.

Treatment produced pronounced immune modulation and ER stress signatures. In the CT‑26 model, therapy increased CD4+ and CD8+ T‑cell infiltration, reduced tumor‑associated macrophages and regulatory T cells, and induced hallmarks of immunogenic cell death. Tumor cells showed upregulation of ER stress pathways (IRE1α/XBP1s and PERK/eIF2α/CHOP), consistent with disrupted proteostasis. These biomarker changes correlated with improved tumor control and resistance to rechallenge, linking pharmacodynamic shifts to antitumor efficacy.

Biodistribution analysis confirmed preferential tumor accumulation with minimal off‑target organ exposure. Hematology, serum biochemistry, and histopathology panels revealed no significant systemic toxicity at efficacious dose ranges, and tolerability windows were defined below observed toxicity thresholds. Co‑delivery of miRNA, the TLR7 agonist, and small‑molecule cargo did not meaningfully increase systemic safety signals versus single‑agent controls within the tested regimens. These preclinical safety and distribution findings support further translational development while remaining preliminary.