Reshaping Intratumoral Mononuclear Phagocytes with Antibody‐Opsonized Immunometabolic Nanoparticles

Abstract Mononuclear phagocytes (MPs) are vital components of host immune defenses against cancer. However, tumor‐infiltrating MPs often present tolerogenic and pro‐tumorigenic phenotypes via metabolic switching triggered by excessive lipid accumulation in solid tumors. Inspired by viral infection‐mediated MP modulation, here enveloped immunometabolic nanoparticles (immeNPs) are designed to co‐deliver a viral RNA analog and a fatty acid oxidation regulator for synergistic reshaping of intratumoral MPs. These immeNPs are camouflaged with cancer cell membranes for tumor homing and opsonized with anti‐CD163 antibodies for specific MP recognition and uptake. It is found that internalized immeNPs coordinate lipid metabolic reprogramming with innate immune stimulation, inducing M2‐to‐M1 macrophage repolarization and tolerogenic‐to‐immunogenic dendritic cell differentiation for cytotoxic T cell infiltration. The authors further demonstrate that the use of immeNPs confers susceptibility to anti‐PD‐1 therapy in immune checkpoint blockade‐resistant breast and ovarian tumors, and thereby provide a promising strategy to expand the potential of conventional immunotherapy.


Figure S1 .
Figure S1.The size distribution of MSNs in TEM.Over 80 particles were counted.Insert: TEM image of MSNs.

Figure S2 .
Figure S2.(a) UV-vis absorption spectra from CTS at various concentrations.(b) CTS standard curve.The absorbance of CTS at 450 nm was measured.A linear fit was applied to calculate the CTS concentration.(c) The loading efficiencies of CTS at various mass ratios of CTS to MSNs.

Figure S3 .
Figure S3.Stability of p(I:C) in CTS/p(I:C)-M.Left panels: agarose gel electrophoresis of free p(I:C) and CTS/p(I:C)-M before and after the treatment with 10% serum (a) or 1 mU RNase A (b). Right panels: quantification of undegraded p(I:C).Data are represented as mean ± SD (n = 3).Student's t-test, ***P <0.001.

Figure S12 .
Figure S12.(a) RT-PCR analysis of CD163 expression in TAMs, DCs and non-MPs from 4T1 tumors.Data are represented as mean ± SD (n = 4).(b) The co-localization of different forms of immeNPs (labeled by FAM, green) with the TAMs (labeled by anti-CD206, red) in 4T1 tumor sections from inoculated mice.Scale bars, 30 μm.

Figure S13 .
Figure S13.Tissue distribution of the immeNPs.(a) The ex-vivo fluorescence imaging of major organs and tumors after intravenous injection of CTS/p(I:C)-M Cy5.5 and CTS/p(I:C)-M Cy5.5 MA.(b) Quantitative analysis of the fluorescent intensities of major organs and tumors in panel (a).Data are represented as mean ± SD (n = 3).Student's t-test, ns means not significant, ***P < 0.001.

Figure S17 .
Figure S17.The in-vivo bioluminescence imaging of 4T1 tumor-bearing mice at various time points.

Figure S19 .
Figure S19.H&E staining of major organs collected from indicated groups.Scale bars =

Figure S24 .
Figure S24.The in-vivo bioluminescence imaging of ID8 tumor-bearing mice at various time points.