Localised Autophagy Inhibition by Nanodiamonds Potentiates Arsenic Therapy With Favourable Safety Profile in Solid Tumours

Arsenic trioxide (ATO) shows limited efficacy against solid tumours, largely because it induces protective autophagy that attenuates its pro-apoptotic activity. Our previous studies established that nanodiamonds (NDs) function as nanoparticle autophagy inhibitors (NAPIs) when delivered systemically, markedly enhancing ATO efficacy in orthotopic liver tumour models by blocking NUPR1-mediated autolysosomal clearance. However, systemic administration remains inefficient in modulating the local autophagic microenvironment within tumours. Here we developed an interventional strategy based on intratumoral injection to assess the feasibility and biosafety of locally blocking autophagic flux while substantially reducing the required ATO dosage, thereby maximising the synergistic anti-tumour effects of NDs and ATO. In HepG2 hepatocellular carcinoma cells, NDs markedly blocked the late stage of autophagic flux, thereby significantly amplifying ATO-induced apoptosis. In a subcutaneous xenograft liver cancer mouse model, intratumoral co-administration of NDs with low-dose ATO achieved ~91% tumour inhibition and effectively eliminated the systemic toxicity associated with high-dose ATO monotherapy. Notably, the synergistic antitumor effect was independent of increased intratumoral ATO accumulation and was driven instead by targeted modulation of the autophagic pathway. Collectively, this study demonstrates a mechanism of localised, nanomaterial-mediated autophagy regulation and offers an efficient, safe strategy for interventional therapy of advanced solid tumours.