OICC Press Journal of Nanostructure in Chemistry 2193-8865 16 2 2026 04 30 Cyclodextrin-Linked Corn Starch Nanostructured Microgels as pH-Responsive Nanocarriers for Doxorubicin Delivery in Hepatocellular Carcinoma 10.57647/jnsc.2026.1602.08 EN Shubin Wang Department of General Medicine, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050000, China Teng Pan Department of Oncology, Shijiazhuang First Hospital, Shijiazhuang, Hebei, 050000, China Jiaqi Zhang Department of Hepatobiliary Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050000, China Hao Guo Department of Hepatobiliary Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050000, China Wuhan Yang Department of Hepatobiliary Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050000, China Journal Article 2026 04 30 Hepatocellular carcinoma chemotherapy remains constrained by off-target toxicity and multidrug resistance, underscoring the need for biobased nanostructured carriers capable of tumor microenvironment-responsive drug delivery. Here, we report cyclodextrin-linked corn starch nanostructured microgels prepared by inverse water-in-oil emulsion crosslinking with epichlorohydrin as a sustainable platform for doxorubicin delivery. Systematic variation of the β-cyclodextrin content generated colloidally stable microgels with hydrodynamic diameters in the 215–410 nm range, narrow polydispersity indices (~0.22–0.31) and increasingly negative zeta potentials down to −21.5 mV. Nitrogen sorption, FTIR, XRD and thermal analyses confirmed the formation of mesoporous polymer networks, with the lead formulation (CS-CD-3) exhibiting a BET surface area of 12.45 m²/g and an average pore diameter of 9.8 nm. Doxorubicin loading into these microgels afforded high drug payloads with an encapsulation efficiency of 78.4% for CS-CD-3. In vitro release studies demonstrated pronounced pH-dependent behavior, with only ~24% cumulative release at physiological pH 7.4 versus ~72% at pH 5.0 after 24 h, consistent with the intrinsic pH-dependent ionization of doxorubicin and the associated pH-modulated DOX–β-cyclodextrin host–guest interactions within the microgel network. Kinetic fitting of the pH 5.0 release data (Higuchi and Korsmeyer–Peppas models) indicated diffusion through a hydrated matrix with an additional polymer-relaxation contribution under acidic in vitro conditions (n ≈ 0.62). Blank microgels preserved >90% cell viability in both HepG2 and L02 cells, whereas doxorubicin-loaded CS-CD-3 microgels decreased the IC50 in HepG2 cells from 2.15 ± 0.18 to 0.85 ± 0.12 μg/mL and increased the IC50 in L02 cells from 4.50 ± 0.35 to 8.20 ± 0.65 μg/mL, improving the selectivity index from 2.09 to 9.64. Confocal imaging confirmed efficient endocytic uptake, endo-lysosomal release and enhanced apoptotic nuclear damage. These results highlight nanostructured cyclodextrin–starch microgels as a promising bio-derived nanoplatform for safer, more selective hepatocellular carcinoma chemotherapy.