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Photoacoustic molecular imaging-escorted adipose photodynamic–browning synergy for fighting obesity with virus-like complexes

Abstract

Photodynamic therapy and adipose browning induction are two promising approaches to reverse obesity. The former strategy acts rapidly and locally, whereas the latter has a more gradual and widespread effect. Despite their complementarity, they have rarely been combined and imaged non-invasively in vivo. Here we introduce an adipose-targeting hepatitis B core protein complex that contains a traceable photosensitizer (ZnPcS4 (zinc phthalocyanine tetrasulfonate)) and a browning agent (rosiglitazone) that allows simultaneous photodynamic and browning treatments, with photoacoustic molecular imaging. After intravenous injection in obese mice, the complex binds specifically to white adipose tissues, especially those rich in blood supply, and drives adipose reduction thanks to the synergy of ZnPcS4 photodynamics and rosiglitazone browning. Using photoacoustic molecular imaging, we could monitor the changes induced by the treatment, which included complex activity, lipid catabolism and angiogenesis. Our findings demonstrate the anti-obesity potential of our feedback-based synergic regimen orchestrated by the targeted hepatitis B core complex.

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Scheme 1: Fabrication process of Pat-HBc/RSG&ZnPcS4 and its application in targeted PDB anti-obesity under the navigation of PA molecular imaging.
Fig. 1: Characterization of fabricated Pat-HBc complexes.
Fig. 2: In vitro assessments for cellular uptake and anti-obesity of Pat-HBc/RSG&ZnPcS4.
Fig. 3: Ex vivo and in vivo PAI for tracking fat accumulation of Pat-HBc/RSG&ZnPcS4.
Fig. 4: Fat reduction with the Pat-HBc/RSG&ZnPcS4-PDB regimen under PA surveillance.
Fig. 5: Alterations at the molecular level in adipose tissues after PDB treatment strategy.
Scheme 2: Anti-obesity mechanisms of Pat-HBc/RSG&ZnPcS4-mediated combination therapy.

Data availability

All the datasets in the current study are available from the corresponding author upon reasonable request. Source data are provided with this paper.

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Acknowledgements

This work was financially supported by the National Natural Science Foundation of China (U190420008 and 81922034&91859113) and the Science Fund for Distinguished Young Scholars of Fujian Province (2018J06024). We thank X. Wang for her technical support in immunological experiments, Z. Wu for his guidance in PA data processing and S. Li for his help in PA data collection.

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R.C. and L.N. conceived and designed the study. R.C., S.H., T.L., H.M., W.S. and J.L. carried out the experiments. R.C., S.H., F.D. and J.Z. analysed the data. R.C. wrote the first draft of the manuscript. L.R. and L.N. edited the manuscript. All the authors read and approved the final manuscript.

Corresponding author

Correspondence to Liming Nie.

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The authors declare no competing interests.

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Peer review information Nature Nanotechnology thanks Frank Sainsbury and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended Data Fig. 1 Competition assays.

a,b, Representative confocal microscope images of adipose MECs (a) and mature adipocytes (b) pretreated with/without Pat-HBc for 2 h and further incubated with HBc/RSG&ZnPcS4 or Pat-HBc/RSG&ZnPcS4 for 12 h. Prohibitin was stained with phycoerythrin-conjugated anti-prohibitin antibody (magenta channel). Nuclei were counterstained with DAPI (blue channel). The experiments were repeated three times with similar results. Scale bars, 20 μm.

Extended Data Fig. 2 Safety assessments.

a, Representative H&E stained images of major organs including liver, kidney, heart, lung and spleen in different groups after two treatment cycles. The experiment was repeated three times with similar results. Scale bars, 50 μm. b-j, Serum biochemistry in obese mice after different treatments (n = 7 mice). Serum TP (b), ALT (c) and AST (d) reflect hepatic function. Serum uric acid (e), urea (f) and creatinine (g) reflect renal function. Serum CK (h), CK-MB (i) and LDH (j) reflect cardiac function. Asterisks in c and d denote significant differences compared with the control, RSG, ZnPcS4, RSG&ZnPcS4 and Pat-HBc/ZnPcS4 groups, p < 0.05. k-m, Serum IgG (k), IL-4 (l) and IFN-γ (m) levels indicative of cellular and humoral immune responses in obese mice at designated intervals after tail-vein injection with PBS, OVA, HBc or Pat-HBc (n = 6 mice). Time points for the first injection and the second injection were set on day 0 and day 7, respectively. Asterisks denote a significant difference from the PBS group, p < 0.05. Hash signs denote significant differences compared with the OVA and HBc groups, p < 0.05. All statistical data are expressed as mean ± s.d. Statistical significance was assessed via a one-way ANOVA with Duncan post-hoc test.

Supplementary information

Supplementary Information

Supplementary Figs. 1–27 and Tables 1–4.

Reporting Summary

Supplementary Video 1

3D laser-scanning confocal microscopy for analyzing penetration properties of different ZnPcS4 formulations in MEC spheroids (scan depth: ~240 μm).

Supplementary Video 2

3D PA display of abdominal adipose vessels in the obese mouse of Pat-HBc/RSG&ZnPcS4 group before and after treatment.

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Chen, R., Huang, S., Lin, T. et al. Photoacoustic molecular imaging-escorted adipose photodynamic–browning synergy for fighting obesity with virus-like complexes. Nat. Nanotechnol. 16, 455–465 (2021). https://doi.org/10.1038/s41565-020-00844-6

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