Naturally derived excipients in injectable nanomedicines: a systematic review of pharmacokinetic performance, regulatory readiness, and future quality by design perspectives.

INTRODUCTION: Naturally derived excipients such as lecithin, chitosan, and hyaluronic acid offer biocompatibility for injectable nanomedicines, although material variability may limit clinical translation. This systematic review evaluated pharmacokinetic performance alongside regulatory and quality gaps. METHODS: PubMed, Scopus, Web of Science, and Embase (2002-2025) were searched for nanocarriers (≤500 nm) incorporating naturally derived excipients with pharmacokinetic or physicochemical data. Risk of bias was assessed using SYRCLE, Cochrane RoB 2.0, ROBINS-I, and an adapted Newcastle-Ottawa Scale. Descriptive synthesis was performed due to heterogeneity. The protocol was registered on OSF (10.17605/OSF.IO/6XA5M). RESULTS: Sixty-three studies met inclusion criteria (48 preclinical, 15 clinical). Among preclinical studies reporting pharmacokinetic parameters, median 2.4-fold plasma exposure (n = 15) and 2.9-fold tumor accumulation (n = 18) increases were observed versus free drug. No included studies reported ICH Q8-aligned quality by design (QbD), multivariate modeling, or artificial intelligence. Fewer than 10% reported detailed compositional characterization or impurity profiling relevant to parenteral development. CONCLUSIONS: Naturally derived excipients were associated with pharmacokinetic enhancement, but inconsistent characterization and limited adoption of structured QbD approaches may hinder regulatory translation. Certainty of evidence across outcomes was low, and prospective validation of proposed QbD strategies remains necessary.