Background: Premature drug leakage and inefficient cellular uptake are stand out as considerable hurdles for low drug delivery efficiency in
tumor chemotherapy. Thus, we established a novel drug delivery and transportation strategy mediated by biocompatible
silk fibroin (SF)-coated nanoparticles to overcome these therapeutic hurdles. Methods: we first synthesised a TME-responsive biocompatible nanoplatform constructed of amorphous
calcium carbonate (ACC) cores and SF shells for enhanced
chemotherapy by concurrently inhibiting premature drug release, achieving lysosome-targeted explosion and locally sprayed DOX, and monitoring via PAI, which was verified both in vitro and in vivo. Results: The natural SF
polymer first served as a "gatekeeper" to inhibit a drug from prematurely leaking into the circulation was demonstrated both in vitro and in vivo. Upon encountering TMEs and targeting to the acidic pH environments of lysosomes, the sensitive ACC nanoparticles were gradually degraded, eventually generating a large amount of Ca2+ and CO2, resulting in lysosomal collapse, thus preventing both the efflux of DOX from
cancer cells and the protonation of DOX within the lysosome, releasing multiple hydrolytic
enzyme to cytoplasm, exhibiting the optimal therapeutic dose and remarkable synergetic therapeutic performance. In particular, CO2 gas generated by the pH response of ACC nanocarriers demonstrated their imaging capability for PAI, providing the potential for quantifying and guiding drug release in targets. Conclusion: In this work, we constructed TME-responsive biocompatible NPs by coating DOX-preloaded ACC-DOX clusters with SF via a bioinspired mineralization method for efficient
therapeutics. This functional lysosome-targeted preservation-strategy-based therapeutic system could provid novel insights into
cancer chemotherapy.