Despite significant advancements in anticancer nanotherapeutics, the efficient encapsulation of multiple therapeutic modalities within single nanocarriers remains challenging due to the complex requirements of supramolecular self-assembly and/or chemical modification. These intricate synthesis procedures often impede the clinical translation of promising nanomedicines. In this study, we introduce a cost-effective and straightforward self-assembling cytotoxic nanotherapeutic strategy that enables the noncovalent incorporation of water-insoluble anticancer molecular inhibitors with high drug loading. This was achieved through the lipid conjugation of camptothecin, enabling nanoassembly in aqueous solutions devoid of excipients. These nanoassemblies were further developed into nanovehicles capable of encapsulating a high capacity of structurally diverse cargos, including molecularly targeted agents. Notably, nanoassemblies composed of linoleic acid-conjugated camptothecin and sorafenib demonstrated stability and sustained release of their payloads. The combination nanoparticles exhibited synergistic effects and effectively overcame ABCG2-mediated drug resistance in hepatocellular carcinoma (HCC). Systemic administration of these nanotherapeutics led to sustained tumor growth inhibition in various HCC xenograft-bearing mouse models, including a chemically induced orthotopic HCC model. This innovative supramolecular assembly strategy, which allows a single vehicle to deliver multimodal therapies, shows promise in overcoming drug resistance in human HCC and could be adapted for the development of other injectable nanomedicines, warranting further investigation. STATEMENT OF SIGNIFICANCE: This study advances anticancer nanotherapy by developing a simple and cost-effective self-assembling strategy that enables high loading of multiple water-insoluble chemotherapeutics. Using lipid-conjugated camptothecin, we created stable nanoassemblies capable of synergistically delivering diverse molecularly targeted agents. This combinatory platform effectively overcame therapeutic resistance and demonstrated sustained tumor inhibition in hepatocellular carcinoma-bearing mouse models. This new self-assembling cytotoxic nanotherapeutic strategy has potential applications for the development of other injectable nanomedicines.