Chemo-phototherapeutic co-delivery nanosystems for colorectal cancer: a review

Nanocarrier-based co-delivery has emerged as a rational strategy to address the pharmacokinetic mismatch, spatially heterogeneous drug exposure, and adaptive therapeutic resistance that limit colorectal cancer (CRC) combination therapy. Rather than simply increasing the number of payloads, effective co-delivery systems should create mechanistic coordination between drug ratio control, tumor-selective accumulation, intracellular release, and biological sensitization. This review critically summarizes CRC-related co-delivery platforms, including chemo-chemo combinations, chemotherapy with targeted therapeutics, and chemotherapy integrated with photothermal, photodynamic, magnetothermal, imaging-guided, or immunomodulatory functions. Across these systems, the most compelling designs are those that move beyond passive co-loading: fixed-ratio liposomes preserve synergistic drug exposure; receptor- or peptide-targeted carriers enhance selective uptake; pH-, enzyme-, ROS-, heat-, or magnetic-field-responsive platforms regulate release; and chemo-PDT/PTT systems connect cytotoxic drugs with oxidative stress, mild hyperthermia, immunogenic cell death, or tumor microenvironment remodeling. However, increasing functional integration often introduces a countervailing translational burden, including unclear component-level contribution, heterogeneous EPR-dependent delivery, insufficiently predictive models, long-term safety concerns for inorganic materials, and manufacturing/regulatory complexity. Future progress should shift from maximal multifunctionality toward clinically executable coordination, emphasizing mechanism-defined design, quantitative validation of each functional module, scalable formulation, biomarker-guided patient selection, and clinically relevant CRC models.