Bone-Targeted Nanoparticles Enable Metabolic Reprogramming via cGAS Lactylation Suppression to Restore...

Area of Science:

• Oncology
• Nanomedicine
• Immunometabolism

Background:

• Osteosarcoma (OS) exhibits chemoresistance and immune suppression, limiting cisplatin efficacy.
• Aberrant glycolysis and lactate accumulation in OS promote resistance and impair antitumor immunity via cGAS lactylation.
• Lactate-associated post-translational modification of cGAS (cytosolic 2′,5′-oligoadenylate synthetase) attenuates cGAS-STING signaling.

Purpose of the Study:

• To develop a bone-targeted nanotherapeutic to restore immunometabolic balance in osteosarcoma.
• To co-load inhibitors of glucose transporter 1 (GLUT1) and monocarboxylate transporter 1 (MCT1) to suppress lactate production and transport.
• To evaluate the therapeutic potential of the nanotherapeutic in overcoming chemoresistance and enhancing antitumor immunity.

Main Methods:

• Development of MALss^Gi/A@Mi, a bone-targeted nanotherapeutic co-loaded with GLUT1 inhibitor WZB117 and MCT1 inhibitor BAY8002.
• Utilizing glutathione-responsive release in the reductive tumor microenvironment for targeted drug delivery.
• In vitro and in vivo studies, including patient-derived xenograft models, to assess therapeutic efficacy.

Main Results:

• MALss^Gi/A@Mi effectively inhibited GLUT1 and MCT1, suppressing lactate production and transport in OS.
• Metabolic reprogramming alleviated cGAS lactylation, restoring cGAS-STING signaling and enhancing antitumor immune responses.
• The nanotherapeutic sensitized OS to cisplatin, remodeled the immunosuppressive tumor microenvironment, and suppressed tumor growth, showing efficacy in recurrent OS models.

Conclusions:

• The developed nanotherapeutic MALss^Gi/A@Mi offers a strategy to overcome osteosarcoma chemoresistance by modulating the metabolic-immune axis.
• Targeting aberrant glycolysis and restoring immune function presents a viable approach for treating osteosarcoma, including recurrent cases.
• This nanomaterial-enabled strategy holds significant translational potential for osteosarcoma therapy.