Injectable nanosuspension based on orthoester for synergistic chemo-photothermal/gas therapy in localized cancer treatment

Localized drug delivery system possesses significant potential for enhancing therapeutic efficacy by maximizing drug accumulation at tumor sites while minimizing systemic toxicity. In this study, we developed an injectable pH-responsive nanosuspension (OE-I-m@MTA) integrating chemotherapy, photothermal therapy, and nitric oxide (NO)-mediated gas therapy. An orthoester compound (OE) was synthesized as a liquid excipient. Mitoxantrone (MIT) and the NO donor L-arginine (L-Arg) were loaded into mesoporous silica nanoparticles (MSN), which were further encapsulated by H22 tumor cell membranes to give a biomimetic nanoparticles (m@MTA). Subsequently, m@MTA and indocyanine green (ICG) were dispersed within the OE matrix to form an injectable nanosuspension (OE-I-m@MTA). Upon peritumoral injection, the OE component demonstrated dual advantages: pH-responsive dissolution in the acidic tumor microenvironment and enhanced tissue permeability, synergistically promoting deep tumor penetration of the biomimetic nanoparticles. Under 808 nm laser irradiation, OE-I-m@MTA exhibited triple therapeutic effects, effectively inhibiting the proliferation of cancer cells. This multimodal approach achieved remarkable tumor suppression, with a tumor growth inhibition rate of 93.86 %. The orthoester based nanosuspension provide a novel combinatorial therapeutic paradigm for localized cancer treatment.