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Therapeutic proteins are encapsulated within pH-responsive polymer shells that remain near-neutral at physiological pH but gradually gain positive charge under acidic conditions. This dynamic charge modulation allows nanocapsules to sense pH gradients between healthy and diseased tissues, directing them toward pathological sites. Unlike receptor-mediated targeting that operates over nanometer scales, this receptor-independent approach enables long-range targeting. In vivo models of cancer, chronic inflammation, and acute injury demonstrate selective accumulation of encapsulated proteins at diseased sites, enhancing therapeutic efficacy while reducing systemic toxicity. 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