Ultrasmall platinum nanoclusters: A potent chemotherapeutic drug for cancer-specific DNA damage with optimizing therapeutic efficacy while minimizing systemic toxicity

Platinum chemotherapy drugs, represented by cisplatin, have been widely used in cancer therapy. While they are effective, their use is limited by their adverse effects in long-term administration, especially the lack of selectivity and high systemic toxicity. Encouragingly, molecular-like platinum nanoclusters, as a bridge between nanomedical and small molecular drugs, provide an attractive opportunity to completely change the current status of cancer treatment, mainly due to their unique structural advantages, making them highly efficient and low toxic. Functional modifications offer a promising avenue to enhance template-modified platinum nanoclusters' selectivity and safety, addressing systemic toxicity concerns. Concurrently, leveraging tumor heterogeneity facilitates drug bioactivity via metabolism, thereby augmenting therapeutic efficacy. Herein, we utilized iRGD-modified bovine serum albumin (BSA-iRGD) as the protective molecule to construct platinum nanoclusters drug (PtNC@BSA-iRGD) directly under mild conditions. The new type of chemotherapeutic drug PtNC@BSA-iRGD exhibits excellent antitumor activity in vitro/vivo, in comparison to clinical commercial first-line carboplatin. This powerful antitumor effect is attributed to its selective uptake by tumor cells through receptor-mediated endocytosis. The release of platinum ions inhibits DNA replication by forming DNA-Pt complexes, activates apoptosis pathways, and ultimately induces tumor cell apoptosis. More impressively, compared to first-line platinum chemotherapy drugs, PtNC@BSA-iRGD has superior biocompatibility while possessing higher tumor inhibitory activity in vivo during medication treatment. This feature compensates for the shortcomings of clinical chemotherapy platinum-based drugs. This study provides novel insights into exploring new forms of metal cluster-based platinum drugs with high efficiency for optimizing therapeutic efficacy while minimizing systemic toxicity. [Display omitted] •Developing a high-safety, atomically precise PtNC@BSA-iRGD targeted drug.•In-depth investigation of the antitumor biological activities of PtNC@BSA-iRGD drug both in vitro and in vivo.•Revealing the antitumor mechanism of atomically precise PtNC@BSA-iRGD drugs.•Exploring new forms of metal cluster-based platinum drugs with high efficiency and low systemic toxicity.