Tunable, ultrasensitive pH-responsive nanoparticles targeting specific endocytic organelles in living cells.

In recent years, multifunctional nanoparticles have received considerable attention in many applications such as biosensors, diagnostic nanoprobes, and targeted drug delivery. These efforts have been driven to a large extent by the need to improve biological specificity in diagnosis and therapy through the precise spatiotemporal control of agent delivery. To achieve this goal, continuous efforts have been dedicated to the development of stimuli-responsive nanoplatforms. Environmental stimuli that were exploited include pH, temperature, enzymatic expression, redox reaction, and light. Among these activating signals, pH triggers belong to the most extensively studied stimuli based on two types of differences in pH: a) pathological (e.g. tumor) versus normal tissues and b) acidic intracellular compartments. For example, owing to the unusual acidity of the tumor extracellular microenvironment (pHe 6.5), several pHe-responsive nanosystems were reported to increase the sensitivity of tumor imaging or the efficacy of therapy. To target the acidic endosomal/lysosomal compartments, nanovectors with pH-cleavable linkers were reported to improve payload bioavailability. Furthermore, several smart nanovectors with pH-induced charge conversion were designed to increase drug efficacy. Despite these remarkable advances, specific transport and activation of nanoparticles in different endocytic organelles during endocytosis in living cells is not well documented. The endocytic system comprises a series of compartments that have distinct roles in the sorting, processing, and degradation of internalized cargo. Selective targeting of different endocytic compartments by pH-sensitive nanoparticles is challenging owing to the short nanoparticle residence times (on the order of minutes) and small pH differences in these compartments (e.g. less than 1 pH unit between early endosomes and lysosomes). Herein we report a set of tunable, pH-activatable micellar (pHAM) nanoparticles based on the supramolecular selfassembly of ionizable block copolymer micelles (Figure 1).