Dual Cascade‐Responsive Multifunctional Nanoparticles to Overcome Bacterium‐Induced Drug Inactivation and Enhanced Photodynamic and Chemo‐Immunotherapy of Pancreatic Cancer

Abstract The harsh biological barriers and bacteria within tumor microenvironment not only hinder drug penetration and induce drug inactivation, but also inhibit antitumor immune responses. Here a tumor microenvironment dual cascade‐responsive multifunctional nanoparticle, Gem/Emo@NP@GHA is reported, which is engineered from a hyaluronidase (HAase)‐responsive guanidine group functionalized hyaluronic acid (GHA) shell and a glutathione (GSH)‐responsive biopolymer core (Gem/Emo@NP), that encapsulates anticancer drug gemcitabine (Gem) and two‐photon‐excited photosensitizer emodin (Emo). The constructed Gem/Emo@NP@GHA can specifically target the tumor and subsequently be degraded by HAase‐abundant in the extracellular matrix. Thus, the resulting Gem/Emo@NP achieved size reduction and charge reversal, strengthening deep tumor penetration. Upon internalization, the positively charged Gem/Emo@NP effectively kills intratumor bacteria by inducing membrane depolarization. Furthermore, the high levels of GSH within tumor cells disrupt the disulfide bonds of Gem/Emo@NP, triggering drug release. Thereby, the undecomposed Gem successfully induces tumor cell apoptosis and necrosis. Under laser irradiation, photosensitizer Emo generates high singlet oxygen (¹O₂), further eliminating tumors and intracellular bacteria. More importantly, Gem/Emo@NP@GHA can activate T cell‐mediated immune response, further enhancing antitumor activity. These findings provide a promising approach to treating bacterially infected tumors through the synergistic application of chem‐immunotherapy and two‐photon‐excited photodynamic therapy.