Improved anti-tumour immune response of RBC-camouflaged oxaliplatin-zinc oxide albumin nanoparticles triggering robust activity in colorectal cancer cells.

Red blood cell (RBC)-camouflaged nanocarriers provide a biomimetic strategy to reduce immune clearance and improve tumour-directed drug delivery. Here, we engineered an RBC-camouflaged albumin nanoplatform co-loaded with oxaliplatin (Oxa) and zinc oxide nanoparticles (nZnO), termed C-AlbOxa-nZnO, for colorectal cancer therapy. The optimized formulation exhibited a uniform hydrodynamic size of 139.3 ± 2.5 nm, a zeta potential of -17.6 ± 2.3 mV, efficient Oxa/nZnO loading, good colloidal stability, and pH-responsive Oxa/Zn2+ release, with enhanced release under acidic/reductive tumour-mimicking conditions. RBC membrane cloaking preserved vesicular morphology and key membrane-associated components, including glycoproteins, sialic acid, CD47, CD55, and CD59, while reducing macrophage uptake. In CT26 cells, C-AlbOxa-nZnO enhanced cytotoxicity (IC₅₀ = 4.27 μM), increased caspase 3/7 activation, and induced ICD-associated calreticulin exposure, ATP secretion, and HMGB1 release. These responses promoted M1 macrophage polarization, dendritic cells maturation, and macrophage-mediated phagocytosis of treated tumour cells. The formulation also downregulated CD44 and reduced CT26 adhesion and migration. In CT26 tumour-bearing mice, RBC coating prolonged systemic exposure, reduced RES-associated accumulation, enhanced tumour Oxa deposition, improved antitumour efficacy, and maintained acceptable systemic tolerability. Therefore, C-AlbOxa-nZnO integrates immune-evasive delivery, Oxa/nZnO co-delivery, ICD-associated immune activation, and improved in vivo antitumour performance.