Targeted nanoparticle delivery of irinotecan enhances tumor response to PD-L1 blockade in colorectal cancer

Colorectal cancer (CRC) remains a leading cause of cancer mortality, with limited therapeutic options in advanced stages. CD44v6, a splice variant overexpressed in CRC, promotes tumor progression and immune evasion, representing a relevant target for selective drug delivery. In this work, irinotecan-loaded poly(lactic- co -glycolic acid) (PLGA) nanoparticles functionalized with CD44v6 ligands (Iri@NP-v6) were developed to improve irinotecan delivery and therapeutic responses in CRC. Iri@NP-v6 showed controlled physicochemical properties, high drug loading, and sustained release. In vitro , targeted NPs achieved selective uptake and enhanced cytotoxicity in CD44v6 + CRC cell lines. In immune-stromal co-culture spheroids, Iri@NP-v6 combined with anti-PD-L1 reduced viability, promoted Th1-associated cytokines, and limited tumor-supportive MCP-1 production. While NP monotherapy induced mixed inflammatory signals, PD-L1 blockade redirected this response toward a Th1-dominated profile. In immunocompetent mice with MC38 tumors, combination therapy significantly reduced tumor burden and increased CD4 + and CD8 + T cell infiltration without systemic toxicity. Importantly, free irinotecan triggered broad systemic inflammation, whereas NP-based delivery limited systemic cytokine release while maintaining intratumoral immune activation. These findings demonstrate that CD44v6-targeted irinotecan NPs in combination with PD-L1 blockade, reshape the CRC immune microenvironment while reducing systemic inflammation, supporting their potential as a tumor-selective chemo-immunotherapy platform. This study shows that specially designed nanoparticles can target colorectal cancer cells and deliver chemotherapy more effectively. When combined with immunotherapy, the treatment decreases tumor volume, boosts immune response, and causes no major side effects in mice. These results suggest a promising new approach to improve cancer treatment using targeted nanomedicine.