Carrier-Free Nanoassembly Suppresses Phase Separation via Ribosome-Inspired Crowding Control for Enhanced Chemo-Immunotherapy.

Authors

Xiaoguang Wang, Lisha Cai, Xiaoxiao Zheng, Li Zheng, Hao Liu, Baoming Wang, Liqiang Hu, Shangzhi Xie, Shufen Zhang, Xuemei Lu, Jiayan Mao, Yiliang Lin, Xiang Gao, Jian Li, Xiaoling Xu, Wei Chen

Published in

ACS nano. Jul 13, 2026. Epub Jul 13, 2026.

Abstract

Chemotherapy can induce tumor cell death and stimulate immunity, yet its efficacy is often compromised by the immunosuppressive tumor microenvironment dominated by M2-like tumor-associated macrophages (TAMs). Redirecting TAMs toward an M1-like phenotype through mammalian target of rapamycin (mTOR)-mediated metabolic modulation has therefore emerged as a promising therapeutic strategy. To this end, we developed a carrier-free nanoassembly (SOP) composed of the mTOR inhibitor OSI-027 and the chemotherapeutic agent SN-38. SOP harnesses ribosome-inspired crowding control to suppress liquid-liquid phase separation (LLPS), thereby facilitating M2 reprogramming and enhancing antitumor efficacy. Following intravenous administration, SOP accumulated in tumor tissues with 2-fold greater efficiency than free drugs. Once internalized, SOP released SN-38 to induce tumor cell death and immunogenic responses, while OSI-027 simultaneously inhibited mTORC1/2 signaling and reduced ribosome abundance-key crowding agents driving LLPS. The resulting disruption of LLPS promoted TAM repolarization toward M1, establishing a synergistic interplay between OSI-027 and SN-38. This dual action translated into robust therapeutic outcomes across diverse models, including cell-derived xenografts, patient-derived xenografts, and KPC (LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre) mice. Moreover, SOP suppressed resistance-related gene expression, overcoming chemotherapy resistance. In summary, this carrier-free nanoassembly not only reprograms the immunosuppressive tumor microenvironment but also introduces LLPS suppression as a mechanism for TAM regulation, positioning SOP as a potent platform for enhanced chemo-immunotherapy.

PMID:
42439015
Bibliographic data and abstract were imported from PubMed on 13 Jul 2026.

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