Near-infrared (NIR)-light-triggered photothermal therapy (PTT) is a promising treatment for breast cancer. However, its therapeutic efficiency is often compromised due to the heat-induced up-regulation of heat shock proteins, which confer photothermal resistance. To solve this urgent problem, PEGylated two-dimensional boron nanosheets (B-PEG)—which allow both multimodal imaging and photothermal conversion—were loaded with gambogic acid (GA), which can inhibit heat shock protein 90 (Hsp90). Experimental findings indicated that this combination of B-PEG and GA could serve as an integrated drug delivery system for cancer diagnosis and treatment. It could be used to administer mild PTT as well as chemotherapy for breast cancer, provide improved anti-tumor effects, and reduce the toxicity of PTT, all while inhibiting breast cancer growth. This drug delivery system could offer a novel tool for administering chemotherapy combined with PTT while avoiding the adverse effects of traditional PTT.