Efficient formulation of SN-38 for broad-spectrum chemotherapy remains an unmet medical need. The limited solubility of SN-38 in both aqueous and organic solvents poses a major challenge for formulation development. As a result, the predominant strategy, polymer-SN-38 drug conjugates, often involves complex synthetic procedures and low drug loading (1-5% w/w). Such limitations hinder their large-scale production and clinical translation. In this study, we developed an encapsulation strategy that utilizes the reversible lactone-carboxylate equilibrium of SN-38 to simplify the formulation process and achieve enhanced drug loading. The major issue of SN-38 solubility in organic solvents was effectively addressed by sodium hydroxide (NaOH)-induced conversion of the lactone to the carboxylate form. We have demonstrated that SN-38 carboxylate, once encapsulated within human serum albumin-polylactic acid (HSA-PLA) nanoparticles, retains its reversibility and can be converted back to the active lactone form simply by the addition of hydrochloric acid (HCl). The drug loading capacity of SN-38 in the HSA-PLA nanoparticles was increased to 19% w/w. In vitro cytotoxicity assays confirmed that HSA-PLA (SN-38) nanoparticles exhibited significantly lower IC(50) values (0.5-194 nM) across multiple cancer cell lines compared to the clinical standard, irinotecan (CPT-11), indicating superior potency under physiological conditions. In vivo studies in 4T1 and MDA-MB-231 tumor-bearing mice further validated the enhanced therapeutic efficacy of this formulation. Overall, this study presents a promising alternative strategy for SN-38 delivery via encapsulation rather than polymer-drug conjugation, significantly simplifying the formulation process and enhancing the translational potential of SN-38 for broad chemotherapeutic applications.